Monell Chemical Senses Center

INTERDISCIPLINARY TRAINING IN THE CHEMICAL SENSES

EFFICACY OF BITTER TASTE BLOCKERS ON FLAVOR ACCEPTANCE IN PEDIATRIC POPULATIONS

LEARNING AND OLFACTION: UNDERSTANDING AND ENHANCING A CRITICAL INFORMATION CHANNEL

PHYSIOLOGY OF CALCIUM APPETITE

EVALUATING THE THERAPEUTIC POTENTIAL OF VAGAL CART CIRCUITRY FOR TREATING METABOLIC DISEASE

IMPACT OF DIET COMPOSITION DURING INFANCY ON ENERGY BALANCE, SATIETY AND GROWTH

MODEL FOR SENSITIVE PERIODS IN EARLY FLAVOR LEARNING

INFLAMMATION AND CHEMOSENSORY LOSS - SUMMARY. OVERVIEW. INFLAMMATION AND CHEMOSENSORY LOSS THIS APPLICATION RESPONDS TO PAR-22-025 AND REQUESTS FUNDS FOR A CLINICAL RESEARCH CENTER TO RESEARCH HOW INFLAMMATION CONTRIBUTES TO THE SUSTAINED LOSS OF TASTE AND SMELL IN THE WAKE OF COVID-19. THREE RESEARCH PROJECTS FOCUS ON THE MOLECULAR MECHANISMS OF SMELL AND TASTE LOSS, AND THE ADMINISTRATIVE AND CHEMOSENSORY CLINICAL SERVICES CORE SUPPORTS THE RESEARCH PROJECT INVESTIGATORS WITH A RANGE OF SERVICES, INCLUDING PARTICIPANT RECRUITMENT STRATEGIES LIKE OUTREACH AND EDUCATION COMPONENTS FOR CLINICIANS, PATIENTS, PATIENT ADVOCACY GROUPS, AND POLICYMAKERS. PROJECT 1 EXAMINES PEOPLE WITH AND WITHOUT SUSTAINED CHEMOSENSORY LOSS, INCLUDING CHILDREN, AND HOW IT IS RELATED TO OLFACTORY AND TASTE EPITHELIUM INFLAMMATION. PROJECT 2 EXAMINES THE OLFACTORY TISSUE IN MORE DEPTH IN A SUBSET OF THE SAME PARTICIPANTS; PROJECT 3 IS SIMILAR BUT FOR TASTE. INVESTIGATORS IN PROJECTS 2 AND 3 WILL DEVELOP ORGANOIDS, AND WE WILL CONDUCT EXPERIMENTS TO SEE HOW THESE ORGANOIDS RESPOND TO VARIANTS OF SARS-COV-2 AND OTHER VIRUSES. THE THEME OF LONG COVID UNITES THE PROJECTS, AND SYNERGIES ARISE BY MEASURING PARTICIPANTS IN EACH PROJECT WITH A STANDARD SET OF TOOLS, ALLOWING FOR DIRECT COMPARISONS ACROSS PROJECTS. ALL THE INVESTIGATORS ARE EXPERTS IN THEIR RESPECTIVE FIELDS, AND THE DIRECTOR HAS YEARS OF EXPERIENCE ADMINISTERING LARGE RESEARCH AND TRAINING PROGRAMS. INNOVATION OF THIS PROJECT IS TWO-FOLD: (A) LEVERAGING THE UNFORTUNATE NATURAL EXPERIMENT OF COVID-19 CHEMOSENSORY DYSFUNCTION TO UNDERSTAND THE CHEMICAL SENSES BETTER AND (B) DISSOLVING BOUNDARIES IN TRADITIONAL RESEARCH AIMED AT UNDERSTANDING AND TREATING THIS DYSFUNCTION. THE INVESTIGATORS OF THE CLINICAL RESEARCH CENTER AIM TO ACCOMPLISH WHAT NO SINGLE INVESTIGATOR CAN DO ALONE AS THEY WORK TOWARD UNDERSTANDING AND TREATING SUSTAINED COVID-ASSOCIATED TASTE AND SMELL LOSS AND ITS HEALTH CONSEQUENCES.

DIVERSITY SUPPLEMENT TO DP2AT011965 - PROJECT SUMMARY OUR MODERN FOOD ENVIRONMENT, WITH ITS WIDESPREAD AVAILABILITY OF ENERGY-DENSE, PALATABLE FOODS AND ASSOCIATED CUES, IS THOUGHT TO INTERACT WITH OUR PHYSIOLOGY TO PROMOTE FOOD INTAKE. THIS HAS CONTRIBUTED TO THE DRASTIC INCREASE IN OBESITY IN THE UNITED STATES OVER THE PAST SEVERAL DECADES. HOWEVER, MOST PHARMACOLOGICAL WEIGHT LOSS STRATEGIES TARGET SATIATION PATHWAYS, NOT SENSORY PATHWAYS, AND THEREFORE MAY BE LESS EFFECTIVE AT ELIMINATING EFFECTS OF ENVIRONMENTAL/SENSORY CUES ON FOOD INTAKE. HERE WE PROPOSE TO TAKE A NOVEL APPROACH TO UNDERSTANDING THE DRIVE TO EAT BY EXAMINING THE NEURAL INTEGRATION OF SENSORY AND NUTRITIVE FOOD SIGNALS. FIRST, WE WILL CREATE SENSORY “ENGRAMS” – FUNCTIONAL MAPS OF NEURONS ACTIVATED BY DISCRETE SENSORY STIMULI – AND DETERMINE HOW ACTIVATING OR INHIBITING THESE CIRCUITS CAN INFLUENCE FOOD PREFERENCE. NEXT, WE WILL MONITOR CALCIUM DYNAMICS IN INDIVIDUAL NEURONS TO REVEAL THE ACTIVITY PATTERNS THAT INTEGRATE SENSORY AND NUTRITIVE INFORMATION IN THE BRAIN ACROSS DIFFERENT BODY WEIGHTS. THESE STUDIES WILL REVEAL FUNDAMENTAL PRINCIPLES OF HOW FOOD INFORMATION IS INTEGRATED IN THE BRAIN TO DRIVE FEEDING BEHAVIOR, REVEALING NEW TARGETS FOR THE DEVELOPMENT OF OBESITY THERAPEUTICS. THIS APPLICATION SEEKS FUNDS TO ENABLE MS. ALEXANDRA VARGAS, A FIRST-GENERATION, LOW INCOME, LATINX U.S. CITIZEN TO PERFORM RESEARCH ON THE NEURAL UNDERPINNINGS OF FEEDING BEHAVIOR, ADD MULTIPLE COMPLEMENTARY NEUROSCIENCE TECHNIQUES TO HER TECHNICAL REPERTOIRE, DEVELOP RECEIVE WRITING, PRESENTATION, AND NETWORKING SKILLS THAT WILL MAKE HER COMPETITIVE FOR M.D./PH.D. PROGRAMS IN NEUROSCIENCE. THESE FUNDS WILL FACILITATE MS. VARGAS’ TRANSITION TO A PRE-DOCTORAL TRAINEE SO THAT SHE CAN RECEIVE ADVANCED TRAINING AND TAKE A LEADERSHIP ROLE ON AN NIH-FUNDED PROJECT. TO THIS END, WE HAVE CAREFULLY CRAFTED A TRAINING PLAN THAT WILL FACILITATE MS. VARGAS’ TECHNICAL, INTELLECTUAL, AND CAREER DEVELOPMENT, AND FUNDING OF THIS SUPPLEMENT WILL TRANSITION HER TO THIS INDEPENDENT ROLE THAT WILL PREPARE HER FOR THE RIGORS OF AN M.D./PH.D. PROGRAM IN FALL 2023. OVERALL, THIS FUNDING WILL FACILITATE THE CAREER OF MS. VARGAS, AN EXTREMELY IMPRESSIVE AND TALENTED RISING SCIENTIST, GIVING HER THE OPPORTUNITY TO MAKE MAJOR ADVANCES IN THE FIELDS OF NEUROSCIENCE AND OBESITY WHILE INCREASING DIVERSITY IN NIH HEALTH-RELATED RESEARCH.

DIET-INDUCED MODIFICATION OF SWEET TASTE PERCEPTION AND PREFERENCE: A POTENTIAL STRATEGY TO AID IN POPULATION-WIDE REDUCTION IN SUGAR INTAKE

CORE CENTER FOR CHEMICAL SENSES

CHEMOSENSORY CLINICAL RESEARCH CENTER

UNRAVELING THE HOMEOSTATIC AND HEDONIC CIRCUITS UNDERLYING FEEDING BEHAVIOR AND OBESITY - PROJECT SUMMARY THE STRIKING PREVALENCE OF OBESITY AND ITS ASSOCIATED PERSONAL AND PUBLIC HEALTH CONSEQUENCES HIGHLIGHTS THE IMPORTANCE OF UNDERSTANDING WHY INDIVIDUALS OVEREAT AND GAIN WEIGHT. IT IS WIDELY RECOGNIZED THAT OVEREATING RESULTS FROM A COMBINATION OF HOMEOSTATIC (I.E., NUTRIENT NEED, HUNGER) AND HEDONIC (I.E., PLEASURE, REWARD) DRIVES. WHILE THESE HOMEOSTATIC (E.G., HYPOTHALAMIC) AND HEDONIC [E.G., MIDBRAIN DOPAMINE (DA)] SYSTEMS HAVE BEEN CHARACTERIZED AS DISCRETE DRIVERS OF FOOD INTAKE, THERE IS CONSIDERABLE EVIDENCE THAT THESE SYSTEMS OVERLAP. FOR EXAMPLE, DA SIGNALING IN RESPONSE TO FOOD IS POTENTIATED BY HUNGER, INCREASING THE REWARD VALUE OF FOOD DURING TIMES OF HOMEOSTATIC NEED. OUR RECENT FINDINGS IN RODENT MODELS REVEALED A NEURAL CORRELATE FOR THE INTERACTION BETWEEN HOMEOSTATIC AND HEDONIC SYSTEMS. ACTIVITY IN HUNGER-SENSITIVE, HYPOTHALAMIC AGOUTI-RELATED PROTEIN (AGRP)-EXPRESSING NEURONS POTENTIATES THE DA RESPONSE TO FOOD. CONVERSELY, DA SIGNALING ENHANCES THE HOMEOSTATIC AGRP NEURON RESPONSE TO FOOD. WHAT ARE THE CIRCUITS THROUGH WHICH AGRP AND DA NEURONS INTERACT IN RESPONSE TO FOOD? DO THEY HELP EXPLAIN WHY SOME INDIVIDUALS ARE MORE LIKELY TO OVEREAT AND GAIN WEIGHT? THIS PROPOSAL WILL TEST THE OVERARCHING HYPOTHESES THAT DISTINCT AGRP AND DA NEURON SUBPOPULATIONS MEDIATE THE INTERACTION BETWEEN HOMEOSTATIC AND REWARD SIGNALING AND THAT INDIVIDUAL DIFFERENCES IN AGRP AND DA RESPONSES TO FOOD PREDICT FUTURE WEIGHT GAIN. AIM I EXPERIMENTS WILL DETERMINE THE AGRP NEURON PROJECTION SUBPOPULATIONS THAT POTENTIATE DA RESPONSES TO FOOD. WE WILL LEVERAGE THE ANATOMICAL ORGANIZATION OF AGRP NEURONS, AS WELL AS OPTOGENETIC AND CHEMOGENETIC TECHNOLOGIES, TO INDIVIDUALLY TEST HOW EACH AGRP PROJECTION SUBPOPULATION INFLUENCES FOOD-EVOKED DA SIGNALING. AIM II EXPERIMENTS WILL DETERMINE SITES OF ACTION FOR DA MODULATION OF AGRP NEURON ACTIVITY. WE WILL USE GENETIC AND PHARMACOLOGICAL APPROACHES TO EXAMINE HOW DA PROJECTIONS AND NEUROTRANSMITTER SIGNALING INFLUENCE AGRP NEURON ACTIVITY. AIM III WILL DETERMINE HOW AGRP AND DA ACTIVITY PREDICTS FUTURE OVEREATING AND WEIGHT GAIN. TAKING ADVANTAGE OF THE VARIABILITY IN WEIGHT GAIN IN RESPONSE TO A HIGH-FAT, HIGH-SUGAR DIET, WE WILL DETERMINE IF INDIVIDUAL DIFFERENCES IN NEURAL ACTIVITY IN LEAN MICE PREDICT FUTURE OVEREATING AND THE DEVELOPMENT OF OBESITY. OVERALL, THESE EXPERIMENTS TAKE A UNIQUE APPROACH TO UNDERSTANDING WEIGHT GAIN BY (1) DETERMINING THE NEURAL INTERSECTION OF HOMEOSTATIC AND HEDONIC CIRCUITS THAT HAVE CLASSICALLY BEEN CONSIDERED DISCRETE DRIVERS OF INTAKE AND (2) IDENTIFYING NEURAL ACTIVITY BIOMARKERS TO PREDICT OVEREATING AND OBESITY PREDISPOSITION. ULTIMATELY, RESULTS FROM THE PROPOSED STUDIES WILL REVEAL CELLULAR AND MOLECULAR TARGETS THAT CAN BE LEVERAGED TO DEVELOP OBESITY PREVENTION AND MORE EFFECTIVE WEIGHT LOSS STRATEGIES.

GENETICS OF TASTE PERCEPTION

MECHANISMS OF INFLAMMATION-TRIGGERED TASTE LOSS AND ITS RECOVERY - PROJECT SUMMARY TASTE LOSS CAN LEAD TO MALNUTRITION, WEIGHT LOSS, AND DEPRESSION. IN ADDITION, CHANGES IN TASTE ARE A SYMPTOM OF POOR HEALTH. THIS CYCLICAL RELATIONSHIP BETWEEN TASTE AND HEALTH HIGHLIGHTS THE IMPORTANCE OF RESEARCH AIMED AT UNDERSTANDING TASTE LOSS IN BOTH HEALTH AND DISEASE. RESEARCH ON TASTE LOSS WILL PROVIDE NEW APPROACHES IN THE PREVENTION, DIAGNOSIS, AND TREATMENT OF DISEASE. IT IS WELL-DOCUMENTED THAT INFECTIONS AND AUTOIMMUNE CONDITIONS ARE ACCOMPANIED BY CHANGES IN CHEMOSENSORY PERCEPTION INCLUDING CHANGES IN TASTE. HOWEVER, CURRENTLY WE KNOW LITTLE ABOUT HOW TASTE BUD REGENERATION IS REGULATED, AND THERE IS NO EFFECTIVE TREATMENT FOR TASTE LOSS. OUR RECENT RESEARCH INDICATES THAT INFLAMMATION, CHARACTERIZED BY INDUCTION OF INFLAMMATORY CYTOKINES AND INFILTRATION AND ACTIVATION OF IMMUNE CELLS, CONTRIBUTES SIGNIFICANTLY TO TASTE DYSFUNCTION. WE HYPOTHESIZE THAT INFLAMMATION, PARTICULARLY THROUGH THE ACTION OF THE INFLAMMATORY CYTOKINE INTERFERON- (IFN-), CONTRIBUTES TO TASTE LOSS BY INDUCING CELL DEATH AND INHIBITING TASTE BUD CELL RENEWAL, AND THAT RESOLUTION OF INFLAMMATION PROMOTES TASTE BUD REGENERATION. IFN- CAN BE PRODUCED BY VARIOUS TYPES OF IMMUNE AND NONIMMUNE CELLS IN RESPONSE TO INFECTIONS AND AUTOIMMUNITY. ITS LEVELS IN TASTE TISSUES ARE MARKEDLY INCREASED IN AN AUTOIMMUNE DISEASE MODEL WITH TASTE LOSS. YET, WHETHER IFN- DIRECTLY CONTRIBUTES TO TASTE LOSS HAS NOT BEEN DETERMINED. IN THIS PROJECT, WE PROPOSE TO INVESTIGATE THE ROLE OF INFLAMMATION, ESPECIALLY IFN-, IN TASTE LOSS USING BOTH A TRANSGENIC APPROACH AND A CLINICALLY RELEVANT RESPIRATORY VIRAL INFECTION MODEL. WE WILL THEN USE THESE TASTE LOSS MODELS TO STUDY THE MECHANISMS OF TASTE BUD REGENERATION. THIS RESEARCH WILL TEST MECHANISTIC HYPOTHESES OF HOW INFLAMMATION AND INFECTION CAUSE TASTE LOSS, AND HOW TASTE RESPONSES RECOVER. TO UNDERSCORE THE IMPORTANCE OF RESEARCH INVESTIGATING THE LINK BETWEEN INFLAMMATION, DISEASE, AND TASTE LOSS, A CONSIDERABLE NUMBER OF COVID-19 PATIENTS EXPERIENCE TASTE DYSFUNCTION. ALTHOUGH MOST CASES OF TASTE LOSS ARE TEMPORARY, INCLUDING TASTE LOSS ASSOCIATED WITH SARS-COV-2 INFECTION, LONG-TERM TASTE LOSS CAN OCCUR IN SOME PATIENTS. THUS, INSIGHTS FROM THIS RESEARCH WILL BE INFORMATIVE TO BETTER UNDERSTAND TASTE LOSS IN GENERAL, AS WELL AS TASTE LOSS ASSOCIATED WITH COVID-19.

THE ROLE OF T1R TASTE RECEPTORS IN GUSTATION

FUNCTIONAL CHARACTERIZATION OF ENDOCRINE TASTE CELLS

NEURONAL REGULATION OF ADULT TASTE STEM CELLS

PREDICTING HUMAN OLFACTORY PERCEPTION FROM MOLECULAR STRUCTURE

DENDRITIC SIGNALING IN THE OLFACTORY BULB

MAPPING GENES FOR ADIPOSITY IN MICE

ROLE OF METABOLIC SENSING IN HUMAN SWEET TASTE

PERCEPTUAL EFFECTS OF GENETIC VARIATION IN HUMAN ODORANT RECEPTORS

ATYPICAL ANTIPSYCHOTICS: EFFECTS ON HEPATIC GLUCOSE AND LIPID METABOLISM IN HUMAN

THE ROLES AND FUNCTIONS OF OLFACTORY TRANSDUCTION CHANNELS IN THE ODORANT RESPONSE

COMPARATIVE GENETICS OF SWEET TASTE IN CARNIVORA

MECHANISMS OF INFLAMMATION-ASSOCIATED TASTE DISORDERS

FUNCTIONAL CHARACTERIZATION OF ADULT TASTE STEM CELLS

MOLECULAR GENETIC INVESTIGATION OF TASTE SENSATION

MOLECULAR GENETICS OF FAT TASTE

ROLES OF ASCL1 FOR GENERATION AND DIFFERENTIATION OF TASTE CELLS

PATHWAYS AND GENES OF SWEET TASTE CELLS

GENETIC CONTROLS OF MINERAL CONSUMPTION

GENETICS OF TASTE PREFERENCES

DYNAMIC ASPECTS OF OLFACTORY SIGNAL TRANSDUCTION

ROLE OF TASTE SIGNALING ELEMENTS IN ENTEROENDOCRINE CELLS

ORAL COMPLEX CARBOHYDRATE SENSING

SCENTINEL: A RAPID SMELL TEST FOR COVID-19 SURVEILLANCE - PROJECT SUMMARY SMELL LOSS IS A PREDOMINANT SYMPTOM OF COVID-19, AND INITIAL EVIDENCE BASED ON SELF-REPORTS SUGGESTS THAT CHEMOSENSORY LOSS IS A SENSITIVE PREDICTOR OF COVID-19 IN THE GENERAL POPULATION, MORE SO THAN FEVER. HOWEVER, GIVEN THE NATURAL LACK OF AWARENESS OF CHEMOSENSORY CHANGES, SELF-REPORTS UNDERESTIMATE THE TRUE PREVALENCE OF SMELL LOSS IN PATIENTS WITH COVID-19 BY 20% COMPARED TO AN OBJECTIVE TEST. THEREFORE, WE PROPOSE TESTING AND DEPLOYING A RAPID AND OBJECTIVE MEASURE OF SMELL ABILITY, THE SCENTINEL TEST, INSPIRED BY THE NIH TOOLBOX® ODOR IDENTIFICATION TEST THAT OUR TEAM PREVIOUSLY DEVELOPED. SCENTINEL IS AN INEXPENSIVE, AND CONVENIENT SMELL TEST FOR COVID-19 SURVEILLANCE OF THE POPULATION THAT QUICKLY AND EASILY ASSESSES THREE SMELL LOSS FACTORS: ODOR DETECTION, ODOR INTENSITY, AND ODOR IDENTIFICATION. IT IS DESIGNED FOR PRACTICAL USE IN SEVERAL CONTEXTS, INCLUDING HIGH-DENSITY AREAS SUCH AS COMMUNITY MEDICAL SITES, UNIVERSITIES, SUBACUTE CARE FACILITIES, AND BOTH INDUSTRIAL AND NONINDUSTRIAL WORKPLACES. OUR MULTI-DISCIPLINARY TEAM HAS EXPERTISE IN UNDERSTANDING TASTE AND SMELL, DEVELOPING AND VALIDATING CHEMOSENSORY TESTS, AS WELL AS STUDYING THE BROAD SYMPTOMATOLOGY OF COVID-19. THE GROUP IS LED BY MPI DALTON FROM THE MONELL CHEMICAL SENSES CENTER, AN EXPERT IN HUMAN OLFACTION AND DESIGNING OLFACTORY TESTS; MPI PARMA FROM TEMPLE UNIVERSITY IS AN EXPERT IN COVID-19 SMELL LOSS, IS THE CHAIR OF THE GLOBAL CONSORTIUM FOR CHEMOSENSORY RESEARCH, AND HAS EXPERTISE IN CONDUCTING RESEARCH IN RAPIDLY CHANGING SITUATIONS; DR. SCHALET AND HIS TEAM AT NORTHWESTERN UNIVERSITY AND DR. CHUN AND HIS TEAM AT YALE UNIVERSITY, AMONG THE OTHER ESTABLISHED AND INTERESTED PARTNERS (FOX SUBACUTE NURSING HOMES, HORMEL FOOD). OUR TEAM ALSO INCLUDES THE DIRECTOR OF TECHNOLOGY TRANSFER AT THE MONELL CENTER, DR. O’LEARY, TO EXPLORE POTENTIAL PARTNERS AND EXPAND SCENTINEL DEPLOYMENT NATIONWIDE. DR. REED FROM THE MONELL CHEMICAL SENSES CENTER WILL WORK DIRECTLY WITH THE DATA COORDINATION CENTER, DRAWING ON HER EXPERIENCE IN MANAGING LARGE SHARED NIH DATASETS. ALL WILL WORK CLOSELY WITH THE NIH PROJECT SCIENTIST. THIS PROPOSAL AIMS TO A) FINE-TUNE SCENTINEL’S ABILITY TO PREDICT A POSITIVE COVID-19 DIAGNOSTIC TEST; B) EXAMINE MARGINAL SMELL LOSS AS A SIGN OF THE EARLIEST PHASES OF COVID-19, BEFORE A POSITIVE DIAGNOSTIC TEST; AND C) ASSESS THE TEST’S PSYCHOMETRIC VALIDITY WITH TEST-RETEST RELIABILITY MEASURES AND VALIDATION AGAINST THE NIH TOOLBOX® ODOR IDENTIFICATION TEST. TOGETHER, THESE AIMS WILL ESTABLISH A STANDARDIZED PROTOCOL FOR USE OF SCENTINEL AS A RAPID AND OBJECTIVE SMELL TEST THAT CAN EASILY BE INCORPORATED INTO ONSITE COVID-19 TESTING CENTERS, SCHOOLS, AND WORKPLACES NATIONWIDE. FURTHERMORE, IT WILL PROVIDE KEY INSIGHTS INTO EARLY-ONSET CHEMOSENSORY SYMPTOMS IN RELATION TO A CONFIRMED COVID-19 DIAGNOSIS, PROVIDING A CRUCIALLY NEEDED MEANS TO CONTAIN THE SPREAD OF COVID-19.

VOLTAGE-DEPENDENT ION CHANNELS IN GUSTATION

CORTICAL ODOR PROCESSING FOR SOCIAL RECOGNITION - PROJECT SUMMARY THE SENSE OF OLFACTION ALLOWS ANIMALS TO GATHER CRITICAL INFORMATION ABOUT RESOURCES, DANGERS, AND POTENTIAL SOCIAL INTERACTIONS. A PRIMARY GOAL OF OLFACTORY NEUROSCIENCE IS TO UNDERSTAND HOW NEURAL CIRCUIT OPERATIONS IN THE MAIN OLFACTORY SYSTEM PARSE CHEMICAL SIGNALS IN THE ENVIRONMENT AND CONTRIBUTE TO ADAPTIVE BEHAVIOR. NEURAL CIRCUITS IN PIRIFORM CORTEX (PCX), THE PRIMARY OLFACTORY CORTEX, ARE THOUGHT TO TRANSFORM ELEMENTAL ODOR INFORMATION RECEIVED FROM THE OLFACTORY BULB INTO MORE HOLISTIC ‘ODOR OBJECT’ REPRESENTATIONS THAT SIGNAL THE PRESENCE OF UNIQUE ODOR SOURCES IN THE ENVIRONMENT. THE OLFACTORY SYSTEM DEVELOPED THIS ABILITY OVER THE COURSE OF EVOLUTION IN CONTEXTS WHERE INFORMATION ABOUT THE PRESENCE AND IDENTITY OF OTHER ANIMALS, ESPECIALLY CONSPECIFICS, WAS CRITICALLY IMPORTANT. SUBSTANTIAL PROGRESS HAS BEEN MADE IN UNDERSTANDING REPRESENTATIONS OF NEUTRAL MONOMOLECULAR ODORANTS IN PCX. BY CONTRAST, NOTHING IS KNOWN ABOUT OLFACTORY CORTICAL PROCESSING OF SOCIAL SCENTS. IN SUPPORT OF A SPECIALIZED ROLE IN SOCIAL ODOR PROCESSING, PCX DENSELY EXPRESSES RECEPTORS FOR THE NEUROPEPTIDE OXYTOCIN (OT) INVOLVED IN A WIDE RANGE OF SOCIAL BEHAVIORS. HOWEVER, THE POTENTIAL FOR OT MODULATION ALSO SUGGESTS THAT PCX CIRCUITS MAY OPERATE DIFFERENTLY IN SOCIAL AND NONSOCIAL CONTEXTS. THE OBJECTIVE OF THIS PROPOSAL IS TO UNDERSTAND HOW CORTICAL ODOR PROCESSING CONTRIBUTES TO SOCIAL BEHAVIOR. THE CENTRAL HYPOTHESIS IS THAT OT MODULATES PCX CIRCUIT DYNAMICS IN SOCIAL CONTEXTS TO ALLOW DISTINCT CONSPECIFIC IDENTITY CODING AND SUPPORT SOCIAL RECOGNITION. THE APPROACH IS TO USE CALCIUM IMAGING AND MULTI-ELECTRODE RECORDINGS TO OBSERVE PCX POPULATION RESPONSES DURING SOCIAL ODOR PROCESSING AND TO USE TARGETED PERTURBATIONS OF PCX FUNCTION TO TEST ITS ROLE IN SOCIAL BEHAVIOR. THE RATIONALE IS THAT OBSERVING AND PERTURBING THE SYSTEM AS IT PERFORMS ITS NATURAL ROLE IN AN ADAPTIVE BEHAVIOR PROVIDES THE MOST ACCURATE PICTURE OF PCX’S CAPABILITIES AND CONTRIBUTION TO FITNESS. THE FOLLOWING AIMS ADDRESS THESE GOALS: AIM 1: DETERMINE HOW SOCIAL RECOGNITION INFORMATION IS ENCODED IN PIRIFORM CORTEX. WE WILL IMAGE LARGE POPULATIONS OF PCX NEURONS IN FREELY INTERACTING ANIMALS AND COMPARE DYNAMICS AND CODING PROPERTIES DURING SOCIAL OR NONSOCIAL STIMULUS INVESTIGATION TO TEST OUR HYPOTHESIS THAT DISTINCT CIRCUIT DYNAMICS IN SOCIAL CONTEXTS ENABLE RELIABLE DISCRIMINATION OF INDIVIDUAL SOCIAL IDENTITY. AIM 2: DETERMINE HOW OXYTOCIN MODULATES SOCIAL ODOR PROCESSING IN PIRIFORM CORTEX. WE WILL FIRST MEASURE DYNAMICS OF OT NEURON ACTIVITY DURING SOCIAL INTERACTIONS USING FIBER PHOTOMETRY, AND THEN MATCH THESE DYNAMICS WITH OPTOGENETIC STIMULATION OF OT NEURONS WHILE RECORDING PCX POPULATION RESPONSES TO CONTROLLED PRESENTATION OF SOCIAL ODORS. AIM 3: DETERMINE THE ROLE OF PIRIFORM CORTEX IN INDIVIDUALIZED SOCIAL BEHAVIOR. PCX FUNCTION WILL BE PERTURBED BY CHEMOGENETIC INACTIVATION OR BY DELETION OF OT RECEPTORS TO TEST WHETHER CORTICAL PROCESSING AND MODULATION ARE REQUIRED FOR SOCIAL INTERACTIONS THAT DEPEND ON IDENTIFYING INDIVIDUAL SOCIAL PARTNERS IN PAIRWISE AND GROUP SETTINGS. THIS WORK WILL PROVIDE FUNDAMENTAL INSIGHTS INTO HOW THE OLFACTORY SYSTEM CONTRIBUTES TO ADAPTIVE BEHAVIOR IN NATURAL CONTEXTS.

FINE MAPPING OF MOUSE CHR 2 FOR BODY COMPOSITION GENES

CAUSES OF CAFETERIA-FEEDING OBESITY

INVESTIGATING THE GUT-BRAIN SIGNALING DYNAMICS REGULATING FOOD INTAKE

UNRAVELING THE NEURAL MECHANISMS FOR SATIETY AND WEIGHT LOSS BY GLP1-BASED DRUGS - PROJECT SUMMARY OVER THE LAST SEVERAL DECADES, OBESITY RATES HAVE BEEN RISING, AND RESEARCH HAS FAILED TO SOLVE THIS PUBLIC HEALTH CRISIS. NOW, WE ARE AT THE PRECIPICE OF CHANGE. GLUCAGON-LIKE PEPTIDE-1 (GLP1)-BASED OBESITY DRUGS HAVE EMERGED AS A PROMISING STRATEGY FOR WEIGHT LOSS, AND THEIR UNPRECEDENTED SUCCESS IS TRANSFORMING THE TREATMENT OF OBESITY. DESPITE THEIR POPULARITY, WE HAVE LITTLE UNDERSTANDING OF THE BRAIN MECHANISMS THAT DRIVE THE FOOD INTAKE AND BODY WEIGHT REDUCTION FROM THESE DRUGS. IN OUR PRELIMINARY STUDIES, WE FOUND THAT HINDBRAIN GLP1 RECEPTOR (GLP1R)-EXPRESSING NEURONS ARE NECESSARY AND SUFFICIENT FOR THE EFFECTS OF GLP1-BASED OBESITY DRUGS SUCH AS SEMAGLUTIDE (OZEMPIC®/WEGOVY®). FURTHER, OUR DATA SUGGEST THAT THE NEURAL CIRCUITS THAT MEDIATE THE FOOD INTAKE SUPPRESSION AND THE NAUSEA/AVERSION (THE TOP SIDE EFFECT OF THESE DRUGS) ARE ANATOMICALLY AND FUNCTIONALLY SEPARABLE. SPECIFICALLY, WE IDENTIFIED A POPULATION OF NUCLEUS TRACTUS SOLITARIUS (NTS) GLP1R NEURONS THAT PROJECT TO THE PARAVENTRICULAR HYPOTHALAMUS (PVH) THAT SUPPRESSES FOOD INTAKE AND BODY WEIGHT WITHOUT CAUSING AVERSION. BUILDING ON THESE DATA, THIS PROPOSAL WILL BEHAVIORALLY, PHYSIOLOGICALLY, ANATOMICALLY, AND MOLECULARLY CHARACTERIZE NTSGLP1RPVH NEURONS AS A POTENTIAL TARGET FOR WEIGHT LOSS DRUGS WITH FEWER SIDE EFFECTS. FIRST, WE WILL TEST THE NECESSITY OF NTSGLP1R NEURONS, THEIR RECEPTORS, AND THEIR PROJECTIONS TO THE PVH, IN MEDIATING THE SATIETY AND WEIGHT LOSS EFFECTS OF SEMAGLUTIDE. NEXT, WE WILL DETERMINE THE ENDOGENOUS NEURAL ACTIVITY PATTERNS OF NTSGLP1R NEURONS IN RESPONSE TO GUT-DERIVED SIGNALS AND OBESITY DRUGS, AND HOW THIS ACTIVITY CHANGES IN DIET-INDUCED OBESITY. FINALLY, WE WILL DETERMINE THE INPUTS AND OUTPUTS OF NTSGLP1R NEURONS TO MAP A CIRCUIT FOR NON-AVERSIVE SATIETY. THIS COMPREHENSIVE ANALYSIS OF NTSGLP1RPVH NEURONS WILL UNCOVER A NOVEL NEURAL CIRCUIT FOR FEEDING BEHAVIOR, AND DETERMINE THE SUITABILITY OF THIS POPULATION AS A SELECTIVE TARGET FOR FUTURE DRUG DEVELOPMENT.

TAS::57 3600::TAS ANALYTICAL IDENTIFICATION OF STRESS ODORS IN HUMAN BREATH

MOLECULAR GENETIC DISSECTION OF FOOD TEXTURE PERCEPTION - ABSTRACT FOOD TEXTURE, WHICH INCLUDES THE PHYSICAL PROPERTIES OF FOOD SUCH AS SOFTNESS, HARDNESS, AND VISCOSITY, CONVEYS VITAL INFORMATION ABOUT THE WHOLESOMENESS AND PALATABILITY OF FOOD. ANIMALS TEND TO PREFER SOFT FOOD OVER HARD FOOD, LARGELY BECAUSE SOFT FOOD IS MORE EASILY CHEWED AND DIGESTED. FOOD TEXTURE IS DETECTED MAINLY THROUGH MECHANORECEPTORS IN TASTE ORGANS. ONCE THE MECHANORECEPTORS ARE ACTIVATED BY FOOD TEXTURE DURING CHEWING, THE MECHANOSENSORY NEURONS IN THE TONGUE CONVEY FOOD TEXTURE INFORMATION TO THE BRAIN. THERE, FOOD TEXTURE INFORMATION IS CONSOLIDATED WITH THE CHEMOSENSORY FEATURES OF FOOD, SUCH AS SWEETNESS AND BITTERNESS, TO TRIGGER APPROPRIATE FEEDING BEHAVIORS. USING THE FRUIT FLY, DROSOPHILA MELANOGASTER, AS A MODEL ORGANISM, OUR WORK ESTABLISHED THAT THE TRANSMEMBRANE CHANNEL-LIKE (TMC) PROTEIN, TOGETHER WITH A TYPE OF MECHANOSENSORY CELL THAT IS MOLECULARLY MARKED BY TMC, ORCHESTRATES FOOD TEXTURE SENSATION. TO FURTHER DECIPHER THE MOLECULAR AND NEURAL BASES OF FOOD TEXTURE PERCEPTION, WE PROPOSE THREE FUNDAMENTAL GOALS: (1) DETERMINE THE COUPLING BETWEEN FLY TETRASPAN MEMBRANE PROTEIN OF HAIR CELL STEREOCILIA (TMHS) AND TMC IN FOOD TEXTURE SENSATION; (2) DECIPHER THE NEUROMODULATORY MECHANISMS UNDERLYING FOOD TEXTURE PERCEPTION; AND (3) DECIPHER THE NEURAL MECHANISMS GOVERNING THE CROSS-MODAL INTERACTION BETWEEN FOOD CHEMOSENSATION AND MECHANOSENSATION. SINCE FEEDING RESPONSES TO FOOD TEXTURE ARE FAIRLY WELL CONSERVED BETWEEN FLIES AND MAMMALS, OUR PROPOSED RESEARCH TO DEFINE THE MOLECULAR, CELLULAR, AND NEURAL CIRCUIT UNDERPINNINGS OF FOOD TEXTURE SENSATION IN FLIES MAY YIELD FUNDAMENTAL INSIGHTS TO GUIDE RESEARCH ON FOOD TEXTURE PERCEPTION IN MAMMALS, INCLUDING HUMANS.

IMPROVEMENT TO THE ANIMAL FACILITY HVAC SYSTEM AT THE MONELL CHEMICAL SENSES CENTER

VARIABILITY IN THE HUMAN ODORANT RECEPTOR REPERTOIRE

TRIGEMINAL MODULATION OF OLFACTORY RESPONSES IN THE MAIN OLFACTORY EPITHELIUM

EXPLORING THE MOLECULAR AND CELLULAR BASIS OF FOOD TEXTURE SENSATION IN DROSOPHILA

NASAL SOLITARY CHEMOSENSORY CELLS LINKING IRRITATION TO INFLAMMATION

ODOR PROCESSING: DIFFERENCES DETERMINED BY ORIGIN OF ODORANTS

NEW GENETIC TRACERS FOR CONCURRENT LABELING OF MULTIPLE GUSTATORY NEURAL PATHWAYS

GENETIC CAUSES OF CONGENITAL ANOSMIA

CASR, THE CALCIUM-SENSING RECEPTOR: FUNCTION AS A TASTE RECEPTOR

NON-INVASIVE RECORDING FROM THE HUMAN OLFACTORY BULB

SINGLE CELL ANALYSIS OF SALT TRANSDUCTION

DOES CALCIUM CONSUMPTION INFLUENCE SALTY TASTE PERCEPTION

LEICA STELLARIS 5 CONFOCAL MICROSCOPE - PROJECT SUMMARY/ABSTRACT THE IMAGING FACILITY AT THE MONELL CHEMICAL SENSES CENTER IS REQUESTING FUNDS TO PURCHASE A LEICA STELLARIS 5 CONFOCAL MICROSCOPE TO SUPPORT NIH-FUNDED RESEARCH. THE MONELL CENTER IS THE WORLD’S ONLY INDEPENDENT, NONPROFIT INSTITUTE DEDICATED TO INTERDISCIPLINARY BASIC RESEARCH ON THE CHEMICAL SENSES OF TASTE, SMELL, GUT SENSING, AND CHEMICAL IRRITATION, AS WELL AS THE RELATIONSHIP BETWEEN THESE SENSES AND NUTRITION, HEALTH, AND WELL- BEING. RECENT REPORTS THAT TASTE AND SMELL LOSS ARE EARLY SYMPTOMS OF COVID-19 ARE AN EXAMPLE OF THE INCREASING IMPORTANCE OF THIS RESEARCH. OUR NIH-FUNDED SCIENTISTS WILL USE THE STELLARIS 5 CONFOCAL SYSTEM TO COLLECT IMAGING DATA FROM THE NASAL CAVITY, TONGUE, TASTE ORGANOIDS, AND BRAIN TO GENERATE MOSAIC COMPILATIONS FOR QUANTITATIVE ANALYSIS, TO MAP FINE PROJECTIONS WITHIN AND BETWEEN SENSORY SYSTEMS, AND TO PERFORM LIVE FUNCTIONAL IMAGING STUDIES. THE MONELL CENTER HAS A STRONG HISTORY OF NIH SUPPORT, AND OUR FACULTY HAVE UNIQUE EXPERTISE THAT ATTRACTS NATIONAL AND INTERNATIONAL COLLABORATORS. IN THIS APPLICATION, WE PROVIDE STRONG JUSTIFICATION FOR THIS EQUIPMENT REQUEST BY DESCRIBING HOW IT WILL REPLACE OUR CURRENT 18-YEAR-OLD LEICA SP2 CONFOCAL SYSTEM IN OUR IMAGING FACILITY, WHICH WILL IN TURN ADVANCE SCIENTIFIC DISCOVERY BY OUR NIH-FUNDED SCIENTISTS. THE NIH- FUNDED PROJECTS WE DESCRIBE IN THIS APPLICATION REPRESENT A BROAD ARRAY OF CHEMOSENSORY RESEARCH TOPICS IN THE OLFACTORY, GUSTATORY, AND CENTRAL NERVOUS SYSTEMS. THE REQUESTED LEICA STELLARIS 5 CONFOCAL SYSTEM WILL BE HOUSED IN OUR IMAGING FACILITY, PART OF MONELL’S HISTOLOGY AND CELLULAR LOCALIZATION CORE THAT PROVIDES TRAINING AND SERVICES TO ALL SCIENTISTS, POSTDOCTORAL TRAINEES, TECHNICAL STAFF, UNDERGRADUATES, AND VISITING SCIENTISTS AT THE MONELL CENTER. ESTABLISHED IN 2011 WITH SUPPORT FROM AN NIH P30 CENTER CORE GRANT, THE HISTOLOGY AND CELLULAR LOCALIZATION CORE HAS BEEN IN OPERATION FOR 9 YEARS. SINCE THE HISTOLOGY CORE’S INCEPTION, THE MONELL CENTER HAS CONTRIBUTED SUBSTANTIAL INSTITUTIONAL FUNDS TO MAINTAIN AND OPERATE THE CORE. IN THIS SPIRIT, THE MONELL CENTER HAS AGREED TO COMMIT A GENEROUS AMOUNT OF FUNDING TOWARD THE UPGRADE, INSTALLATION, OPERATION, AND MAINTENANCE OF THE INSTRUMENT REQUESTED IN THIS APPLICATION. OVERALL, OBTAINING FUNDING FOR THE LEICA STELLARIS 5 CONFOCAL MICROSCOPE WILL REVOLUTIONIZE MICROSCOPY IN THE IMAGING FACILITY AT THE MONELL CENTER. IN ADDITION TO ITS INTEGRAL ROLE IN COMPLETION OF THE CURRENT NIH-FUNDED PROJECTS, WE WILL USE THE INSTRUMENT TO DEVELOP NOVEL RESEARCH APPROACHES, FOSTER NEW GRANT APPLICATIONS, AND RECRUIT NEW INVESTIGATORS TO THE MONELL CENTER. ACQUISITION OF THIS TECHNOLOGY WILL VASTLY IMPROVE RESEARCH PRODUCTIVITY AND DATA QUALITY, EXPANDING THE SCOPE OF CHEMOSENSORY RESEARCH AT MONELL.

EARLY HUSBANDRY INFLUENCES ON ADULT PHENOTYPE

THE CHOLINERGIC ANTI-INFLAMMATORY PATHWAY IN HUMAN OBESITY AND INSULIN RESISTANCE

SWEET TASTE RECEPTORS AND GLUCOSE METABOLISM IN HEALTHY AND T2DM HUMANS

PARKINSON?S DISEASE BIOMARKERS IN HUMAN OLFACTORY CLEFT MUCUS - PROJECT SUMMARY EARLY DIAGNOSIS OF PARKINSON’S DISEASE (PD) REMAINS A BIG CHALLENGE, AS CLINICIANS ARE STILL LACKING RELIABLE BIOMARKERS. PD PATIENTS ARE TYPICALLY DIAGNOSED WHEN THEY HAVE ALREADY DEVELOPED MOTOR DEFICITS, INDICATING SIGNIFICANT LOSS OF DOPAMINERGIC NEURONS IN THE SUBSTANTIA NIGRA HAS ALREADY OCCURRED. OLFACTORY IMPAIRMENT IS ONE OF THE EARLIEST SYMPTOMS OF PD, OFTEN OCCURRING SEVERAL YEARS BEFORE MOTOR DEFICITS. LEWY BODIES, THE HISTOPATHOLOGICAL HALLMARKS OF PD, ACCUMULATE IN THE OLFACTORY BULB IN EARLY STAGES OF PD. RECENT EVIDENCE INDICATES THAT ABERRANT A-SYNUCLEIN (A-SYN), THE MAIN PROTEIN COMPONENT OF LEWY BODIES, CAN PROPAGATE TRANSNEURONALLY FROM THE OLFACTORY BULB, FURTHER SUGGESTING THE CRITICAL ROLE OF THE OLFACTORY SYSTEM IN PD PATHOGENESIS. HOWEVER, TO DATE, HUMAN OLFACTORY TISSUE HAS NOT BEEN COMPREHENSIVELY EXAMINED TO IDENTIFY MOLECULAR BIOMARKERS FOR PD. THE GOAL OF THIS R21 PROJECT IS TO IDENTIFY PD BIOMARKERS IN HUMAN OLFACTORY CLEFT MUCUS. OLFACTORY SENSORY NEURONS ARE CONCENTRATED IN THE SUPERIOR TURBINATE OF THE NOSE, PROJECTING AXONS TO THE OLFACTORY BULB IN THE BRAIN. OUR RECENT PROTEOMICS STUDIES USING HUMAN OLFACTORY CLEFT MUCUS, A BIOFLUID COVERING THE SURFACE OF THE OLFACTORY MUCOSA, IDENTIFIED SEVERAL WELL-ESTABLISHED PD-ASSOCIATED PROTEINS, INCLUDING A-SYN, DJ-1, AND INFLAMMATORY BIOMARKERS. PRELIMINARY STUDIES OF A PD PATIENT COHORT SHOWED THAT THE RATIO OF A-SYN TO DJ-1 AND LEVELS OF CERTAIN INFLAMMATORY BIOMARKERS ARE SUBSTANTIALLY ELEVATED IN THE OLFACTORY MUCUS OF PD PATIENTS COMPARED TO AGE-MATCHED CONTROLS. PRELIMINARY DATA ALSO SHOWED THAT THE A- SYN/DJ-1 RATIO DISTINGUISHES PD PATIENTS FROM CONTROL SUBJECTS WITH HIGH SENSITIVITY AND SPECIFICITY, SHOWING STRONG BIOMARKER POTENTIAL. HERE WE PROPOSE TO RECRUIT ADDITIONAL PATIENTS WITH EARLY OR ADVANCED PD, AS WELL AS AGE-MATCHED CONTROLS. WE WILL USE A MINIMALLY INVASIVE METHOD ESTABLISHED BY OUR RESEARCH TEAM TO COLLECT OLFACTORY CLEFT MUCUS. WE WILL CONDUCT IMMUNOASSAYS TO DETERMINE LEVELS OF A-SYN, DJ-1, AND MULTIPLE INFLAMMATORY BIOMARKERS. WE WILL TEST THE HYPOTHESIS THAT THE RATIO OF A-SYN TO DJ-1 IS A RELIABLE BIOMARKER FOR PD. FURTHERMORE, WE WILL USE MACHINE LEARNING APPROACHES TO OPTIMIZE OLFACTORY BIOMARKERS FOR PD PROGRESSION. THIS MULTIDISCIPLINARY PROJECT BRINGS TOGETHER INVESTIGATORS WITH EXPERTISE IN OLFACTION, PD PATHOLOGY, INFLAMMATION, AND MACHINE LEARNING. OUR RESEARCH MAY HAVE A MAJOR IMPACT ON PATIENT CARE BY IMPROVING EARLY AND ACCURATE DIAGNOSIS OF PD.

"ODOR SIGNALS OF IMMUNE ACTIVATION AND CNS INFLAMMATION"

SUPER-SENSING OF HUMAN AND ENVIRONMENTAL ODORS BY OPTIMIZED ODOR SENSOR ARRAYS

LABMASTER: FOOD AND WATER INTAKE, ACTIVITY AND METABOLIC RATE

MONELL SCIENTIST ENTREPRENEURIAL PROGRAM FOR HEALTHY AGING (MSEP-HA) - LOSS OF SMELL IS A PART OF NORMAL AGING FOR SOME PEOPLE, BUT PREMATURE SMELL LOSS IS ALSO A BIOMARKER OF NEURODEGENERATIVE BRAIN DISEASES. THERE IS A NEED, AND THUS AN OPPORTUNITY, TO DEVELOP PRODUCTS SUCH AS STANDARDIZED SMELL TESTS THAT WILL BENEFIT NOT ONLY BIOMEDICAL RESEARCH (E.G., AS AN EARLY MEASURE IN CLINICAL TRIALS FOR DISEASES LIKE ALZHEIMER'S) BUT ALSO STANDARDS OF CLINICAL CARE (E.G., AS A ROUTINE PART OF AN ANNUAL PHYSICAL EXAM). WE NEED LEADERS TRAINED IN SCIENCE AND BUSINESS TO TAKE FULL ADVANTAGE OF THIS OPPORTUNITY. OUR MONELL SCIENCE ENTREPRENEURSHIP PROGRAM FOR HEALTHY AGING (MSEP-HA) AIMS TO SELECT PARTICIPANTS WHO ARE LIKELY TO BECOME LEADERS IN THEIR FIELD AND RECEIVE TRAINING AT THE INTERSECTION OF BASIC AND TRANSLATIONAL RESEARCH AND ENTREPRENEURSHIP. WE AIM TO RECRUIT GRADUATE STUDENTS AND POSTDOCTORAL RESEARCHERS (WE WILL PROVIDE A STIPEND FOR HOUSING AND TRAVEL) TO RECEIVE AN EDUCATIONAL EXPERIENCE IN THE NIA MISSION AREA AND PROMOTE THEIR FUTURE INDEPENDENT BIOMEDICAL VENTURES. SIX MSEP-HA PARTICIPANTS ANNUALLY WILL GAIN SKILLS IN INTELLECTUAL PROPERTY, REGULATORY AND REIMBURSEMENT PATHWAYS, AND MARKET NEEDS IDENTIFICATION, USING OUR RECENT EXPERIENCE IN DEVELOPING THE SCENTINEL SMELL TEST. AIDED BY 16+ SCIENCE FACULTY MEMBERS AND 16+ ENTREPRENEURIAL PROFESSIONALS, THE 3-WEEK INTRODUCTORY PROGRAM WILL GIVE 105 HOURS OF INSTRUCTION IN SMELL, THE BIOLOGY OF AGING, AND ENTREPRENEURSHIP. PARTICIPANTS WILL DEMONSTRATE THEIR COMMERCIALIZATION INTERESTS IN THESE AREAS WITH A PRESENTATION AT OUR FALL CORPORATE PARTNERS SYMPOSIUM (ATTENDED BY 30+ PARTNERING COMPANIES). THE MSEP-HA WILL CONNECT WITH EXTERNAL FEDERALLY FUNDED PROGRAMS (E.G., NIH'S IDEA REGIONAL TECHNOLOGY TRANSFER ACCELERATOR HUBS) AND LOCAL BUSINESS SKILLS OPPORTUNITIES (E.G., UNIVERSITY CITY SCIENCE CENTER). OUR EVALUATION PLAN, LED BY EXPERIENCED PROFESSIONALS, WILL TEST AND IMPROVE THE NEW PROGRAM'S EFFECTIVENESS. MONELL IS PRIMED TO SPEARHEAD THIS SHIFT IN AGING AND DEMENTIA RESEARCH: OUR 50+ YEARS OF INSTITUTIONAL PARTNERSHIP WITH FOR-PROFIT COMPANIES IN BASIC AND TRANSLATIONAL RESEARCH (INCLUDING OUR CORPORATE PARTNERS PROGRAM) AND OUR 40+ YEARS OF HISTORY IN EDUCATING SCIENTISTS (INCLUDING THE MONELL SCIENCE APPRENTICESHIP PROGRAM, AN ESTABLISHED TRAINING PROGRAM) SHOW OUR COMMITMENT TO SCIENCE-ENTREPRENEURIAL PARTNERSHIPS. THUS, MSEP-HA WILL INTRODUCE A COHORT OF EARLY-CAREER SCIENTISTS TO TOOLS ESSENTIAL FOR ENTREPRENEURIAL ROLES THAT BENEFIT OUR AGING POPULATION.

COLLABORATIVE RESEARCH: RECONSTRUCTING AIRFLOW IN THE NASAL CAVITY OF MAMMALS

RNA PROCESSING MISREGULATION IN KIF5A ALS - PROJECT SUMMARY AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A FATAL NEURODEGENERATIVE DISEASE THAT WAS PREVIOUSLY CONSIDERED MAINLY A DISORDER OF PROTEIN MISLOCALIZATION. HOWEVER, RECENT FINDINGS HAVE UNVEILED A SIGNIFICANT ASSOCIATION OF ALS WITH RNA MISREGULATION. AMONG THE 53 GENES LINKED TO ALS, THE GENE KIF5A HAS RECENTLY GARNERED ATTENTION. KIF5A, A KINESIN MOTOR PROTEIN KNOWN FOR ITS ROLE IN ORGANELLE TRANSPORT, HAS BEEN IMPLICATED IN ALS THROUGH MUTATIONS THAT PURPORTEDLY LEAD TO A GAIN-OF-FUNCTION, RESULTING IN A HYPERACTIVE STATE OF THE PROTEIN. MY RESEARCH HAS UTILIZED MACHINE LEARNING PREDICTIONS ALONGSIDE EXPERIMENTAL APPROACHES TO DEMONSTRATE THAT KIF5A FUNCTIONS AS AN RNA-BINDING PROTEIN. MOREOVER, I FOUND ALS-RELATED MUTATIONS IN KIF5A MODIFY ITS RNA-BINDING PROFILE, UNCOVERING A NOVEL ASPECT OF KIF5A'S INVOLVEMENT IN ALS. MY PRELIMINARY FINDINGS INDICATE THAT KIF5A WITH ALS MUTATIONS EXHIBITS A PREFERENCE FOR BINDING TO MRNA OF HEAT SHOCK PROTEINS AND SEVERAL OTHER GENES ASSOCIATED WITH ALS. I PROPOSE THAT MUTATIONS IN KIF5A CONTRIBUTE TO MOTOR NEURON DEGENERATION BY DISRUPTING RNA PROCESSING. THE PROPOSED RESEARCH ENCOMPASSES THREE OBJECTIVES: (1) TO INVESTIGATE THE IMPACT OF KIF5A ALS MUTATIONS ON THE PROTEOTOXIC PATHWAY, (2) TO EXPLORE THE INTERACTIONS BETWEEN KIF5A AND ALS-ASSOCIATED GENES AND RNA TARGETS, AND (3) TO EVALUATE THE EFFECTS OF KIF5A MUTATIONS ON TRANSCRIPTION, RNA LOCALIZATION, AND RNA-BINDING PROTEIN (RBP)-RNA INTERACTIONS USING SPINAL ORGANOID MODELS. SUCCESS IN THIS PROJECT WILL LAY THE GROUNDWORK FOR INNOVATIVE METHODS AND INSIGHTS INTO THE MISREGULATION OF RNA PROCESSING IN ALS. MY EXPERTISE IN QUANTITATIVE, SINGLE-MOLECULE IMAGING, COMBINED WITH THE YEO LAB'S PROFOUND KNOWLEDGE IN RNA PROCESSING, STEM CELL MODELS AND NEURODEGENERATION, POSITIONS ME UNIQUELY TO LEAD THE PROPOSED RESEARCH. THESE OBJECTIVES WILL ESTABLISH A FOUNDATION FOR MY CAREER AS AN INDEPENDENT RESEARCHER, FOCUSING ON THE MECHANISMS OF RNA TRANSPORT IN NEURODEGENERATIVE DISORDERS.

THE ROLE OF SWEET TASTE GENES IN POSTINGESTIVE ENDOCRINE RESPONSES TO SWEETENERS

MONELL SCIENCE APPRENTICESHIP PROGRAM: INSPIRING BIOMEDICAL CAREERS IN UNDERREPRESENTED UNDERGRADUATES - PROJECT SUMMARY ONLY ABOUT 4% OF BIOMEDICAL SCIENTISTS AT US RESEARCH INSTITUTIONS AND UNIVERSITIES ARE FROM UNDERREPRESENTED (UR) GROUPS, EVEN THOUGH THESE GROUPS MAKE UP 33% OF THE US POPULATION. TO SUPPORT DIVERSIFICATION OF THE BIOMEDICAL WORKFORCE, WITH PARTICULAR FOCUS ON THE FIELD OF THE CHEMICAL SENSES, THE MONELL SCIENCE APPRENTICESHIP PROGRAM (MSAP) HAS A MISSION TO INCREASE PARTICIPATION OF DISADVANTAGED AND/OR UR STUDENTS IN BIOMEDICAL RESEARCH. WE ARE MEETING THIS MISSION: 5 YEARS AFTER PARTICIPATING IN THE MSAP, 15/69 (22%) OF THE COHORT IS PURSUING POSTGRADUATE EDUCATION, MORE THAN 50% HIGHER THAN THE 2021 US CENSUS ESTIMATE OF 14% OF THE GENERAL POPULATION 25 AND OLDER HOLDING A MASTER’S DEGREE OR HIGHER. THROUGH OUR PROPOSED INNOVATIONS FOR MSAP 2.0, WE WILL EXPAND AND ENHANCE THIS PROGRAM’S POSITIVE FOOTPRINT. MSAP 2.0 OFFERS UNDERGRADUATE STUDENTS (AND HIGH SCHOOL STUDENTS, FOR WHOM SUPPORT IS NOT REQUESTED) TRAINING AT MONELL CENTER, WHOSE MISSION IS TO IMPROVE HEALTH AND WELL-BEING BY ADVANCING THE SCIENTIFIC UNDERSTANDING OF TASTE, SMELL, AND RELATED SENSES. THE 16 FACULTY MEMBERS PARTICIPATING IN THE MSAP HAVE DIVERSE SCIENTIFIC BACKGROUNDS AND CONDUCT COLLABORATIVE RESEARCH USING METHODS SPANNING SUCH DISCIPLINES AS ELECTROPHYSIOLOGY, MOLECULAR BIOLOGY, GENETICS, ANALYTICAL CHEMISTRY, AND PSYCHOPHYSICS (IN BOTH HUMANS AND ANIMALS). MSAP 2.0 OFFERS FULL-TIME, PAID APPRENTICESHIPS THAT INCLUDE 8 SUMMER WEEKS OF STRUCTURED RESEARCH ACTIVITY WITH A MONELL SCIENTIST, AS WELL AS ENRICHMENT ACTIVITIES THAT INCLUDE LECTURES ON THE MECHANISMS AND FUNCTIONS OF THE CHEMICAL SENSES AND INSTRUCTION ON PUBLIC SPEAKING, WRITTEN COMMUNICATION, HYPOTHESIS TESTING, AND RESPONSIBLE CONDUCT OF RESEARCH. AT THE CONCLUDING CAPSTONE SYMPOSIUM, APPRENTICES PRESENT THEIR RESEARCH FINDINGS TO ALL SCIENTISTS AT MONELL, PEERS, STAKEHOLDERS, TEACHERS, FAMILY, AND FRIENDS. MENTORS ARE SUPPORTED BY DIVERSITY, EQUITY, INCLUSION, AND BELONGING (DEIB) EXPERTS, AND OUR EVALUATION PLAN ENSURES AN INCLUSIVE, SAFE, AND SUPPORTIVE EXPERIENCE FOR THE APPRENTICES. MSAP 2.0 IS STRUCTURED TO SPECIFICALLY MEET THESE GOALS: (1) DEVELOP AND IMPLEMENT A SYSTEMATIC RECRUITMENT PLAN TO DOUBLE UR UNDERGRADUATE PARTICIPATION IN MSAP 2.0; (2) PROVIDE UR UNDERGRADUATES WITH AN INTENSIVE, HANDS-ON BIOMEDICAL RESEARCH EXPERIENCE, A DIDACTIC PROGRAM, AND MENTORSHIP IN THE FIELD OF THE CHEMICAL SENSES; AND (3) DEVELOP AND IMPLEMENT SYSTEMATIC EVALUATION AND LONG-TERM MENTORSHIP AND NETWORKING PLANS TO OPTIMIZE THE IMPACT OF MSAP 2.0 ON FUTURE BIOMEDICAL CAREER CHOICES. THE ACTIVITIES DESCRIBED IN THIS PROPOSAL ARE BOTH A TANGIBLE STEP TOWARD DIVERSIFICATION OF THE WORKFORCE IN BIOMEDICAL SCIENCES, ESPECIALLY THE CHEMICAL SENSES, AND A WAY TO INSPIRE AND PREPARE THE NEXT GENERATION OF SCIENTISTS TO MAKE MEANINGFUL CONTRIBUTIONS TO THE FIELD. OUR 42-YEAR HISTORY OF CONTINUOUSLY RUNNING AND IMPROVING MSAP PROVIDES EVIDENCE TO ANTICIPATE THAT GROWTH AND IMPROVEMENT REPRESENTED BY MSAP 2.0 WILL LEAD TO GREATER FUTURE SUCCESS.

SECONDARY ANALYSES OF RCT DATA ON SENSITIVE PERIODS IN FLAVOR LEARNING AND DIET AMONG BREASTFEEDING DYADS

TARGETED GENOTYPING AND GENE EXPRESSION WITH THE QUANTSTUDIO 12K FLEX

MEASUREMENT OF BODY COMPOSITION IN RATS AND MICE

SECONDARY ANALYSES OF RCT DATA ON INFANT FORMULA AND NUTRITIONAL PROGRAMMING

MD: CONTINUED APPLICATION OF CHEMOSENSORY AND WILDLIFE DAMAGE MANAGEMENTRESEARCH

MECHANISMS OF INFLAMMATION-TRIGGERED TASTE LOSS AND ITS RECOVERY

MECHANISMS OF INFLAMMATION-TRIGGERED TASTE LOSS AND ITS RECOVERY

CONTINUED APPLICATION OF CHEMOSENSORY AND WILDLIFE DAMAGE MANAGEMENT RESEARCH

THE CHEMICAL SENSES PLAY SIGNIFICANT ROLES IN WILDLIFE BEHAVIOR. FOR EXAMPLE, DIET SELECTION IS DEFINED BY THE CHEMOSENSORY PROPERTIES OF A FOOD ITEM AND THE CONSEQUENCES OF INGESTION.

REVISION 1 TO EXTEND AGREEMENT TO SEPTEMBER 29, 2019 AND ADD$28,000 IN FUNDS TO TOTAL THE AWARD TO $115,038. ALL OTHER TERMS AND CONDITIONS REMAIN IN EFFECT.

NASAL AIRFLOW AND ODORANT TRANSPORT: A PREREQUISITE FOR NORMAL OLFACTION

STABLE ISOTOPE BIOMARKER FOR ADDED SUGAR INTAKE AND SWEET TASTE PHENOTYPES IN MOTHER-CHILD DYADS

CA2+ SIGNALING AND EPHAPTIC COUPLING IN OLFACTORY RECEPTOR NEURONS USING LATTICE LIGHT-SHEET MICROSCOPY

MODIFYING SALT TASTE PERCEPTION, PREFERENCE, AND INTAKE IN INDIVIDUALS WITH SMELL LOSS - PROJECT SUMMARY INDIVIDUALS WHO SUFFER FROM A DIMINISHED OR LOST SENSE OF SMELL (HYPOSMIA/ANOSMIA) CONSISTENTLY REPORT FOOD TO BE BLAND AND LESS PALATABLE, RESULTING IN A REDUCTION IN DIET QUALITY AND QUALITY OF LIFE. DESPITE THESE REPORTS, WE HAVE LIMITED KNOWLEDGE ABOUT HOW SMELL LOSS INFLUENCES FOOD PERCEPTION AND PREFERENCES FROM EXPERIMENTAL STUDIES. AS A RESULT, THERE IS MINIMAL DIETARY GUIDANCE FOR H/A INDIVIDUALS. H/A INDIVIDUALS SELF-REPORT PREFERRING SALTIER FOODS AND INCREASING THEIR SALT INTAKE TO COMPENSATE FOR THE LOSS OF SMELL-MEDIATED FOOD FLAVORS. HOWEVER, SALT CONSUMPTION ALREADY EXCEEDS RECOMMENDED LEVELS IN 90% OF THE POPULATION AND CONTRIBUTES TO CARDIOVASCULAR DISEASE; FURTHER INCREASING SODIUM INTAKE CAN HAVE BROAD, NEGATIVE HEALTH IMPLICATIONS. DOCUMENTING SALT PREFERENCES AND INTAKE USING VALIDATED MEASURES WILL HELP GUIDE FUTURE RESEARCH ON IMPROVING FOOD LIKING AND DIET QUALITY IN H/A INDIVIDUALS. THIS PROPOSAL WILL (1) ASSESS DIFFERENCES IN SALT TASTE PREFERENCES, SALT INTAKE, AND APPETITE BETWEEN H/A INDIVIDUALS AND THOSE WITH A NORMAL SENSE OF SMELL (NORMOSMIC) AND (2) DETERMINE THE ACUTE EFFECTS OF CAPSAICIN ON FLAVOR, LIKING, AND SALT TASTE INTENSITY IN H/A COMPARED WITH NORMOSMIC INDIVIDUALS. AIM 1 WILL MEASURE (A) SALT TASTE INTENSITY USING GENERAL LABELED MAGNITUDE SCALES, (B) LIKING USING LABELED HEDONIC SCALES, (C) SALT TASTE PREFERENCES USING THE MONELL FORCED- CHOICE PAIRED COMPARISON TRACKING PROCEDURE, (D) SODIUM INTAKE VIA 24-HOUR URINE SAMPLES, AND (E) APPETITE USING THE POWER OF FOOD SCALE IN H/A INDIVIDUALS WITH LONG-TERM SMELL LOSS (>12 WEEKS) COMPARED WITH NORMOSMIC INDIVIDUALS. THESE DATA WILL HELP GUIDE FUTURE STRATEGIES TO IMPROVE DIET QUALITY IN H/A INDIVIDUALS. AIM 2 WILL TEST WHETHER CAPSAICIN CAN BOOST SALT TASTE INTENSITY IN THIS POPULATION, THUS ESTABLISHING A SENSORY STRATEGY TO AVOID EXCESS SALT FOR FLAVOR BY USING THE SAME SCALES TO MEASURE SALT INTENSITY, OVERALL FLAVOR, AND LIKING. THIS WILL PROVIDE A SENSORY STRATEGY TO REDUCE SALT INTAKE AND IMPROVE DIET QUALITY SPECIFICALLY FOR H/A INDIVIDUALS, FILLING THIS CRITICAL INFORMATION GAP. THIS RESEARCH AIMS TO UNDERSTAND FOOD PREFERENCES AND PERCEPTION RELATED TO SMELL LOSS AND REDUCE SALT INTAKE, WHICH HAS IMPLICATIONS FOR DIET QUALITY AND RISK FOR CARDIOVASCULAR DISEASE, WHICH ALIGNS WITH PRIORITY AREAS 2 AND 4 FOR THE NIDCD. THE CONCURRENT TRAINING PLAN IN PSYCHOPHYSICS AND SENSORY MEASUREMENT WILL COMPLEMENT MY TRAINING IN NUTRITION SCIENCE TO SUPPORT MY LONG- TERM RESEARCH GOAL OF IDENTIFYING SENSORY STRATEGIES TO IMPROVE DIET QUALITY AND REDUCE THE RISK FOR CHRONIC DISEASES.

CONDUCT A STUDY TO TEST THE CONCEPT THAT THE DISEASE STATE OF AN ANIMAL CAN BE DETECTED VIA OLFACTORY CUES.

SALT RESPONSES IN ISOLATED TASTE CELLS

BIOPHYSICAL MODELS OF HUMAN OLFACTORY INTENSITY PERCEPTION - PROJECT SUMMARY/ABSTRACT WE CAN MEASURE THE BRIGHTNESS OF A COLOR AND THE LOUDNESS OF A SOUND BECAUSE WE HAVE RELATED THESE PERCEPTUAL PROPERTIES TO PHYSICAL PROPERTIES. THIS HAS NOT BEEN DONE FOR OLFACTION. KNOWING THE BASIC UNIT OF INTENSITY IS ESSENTIAL TO UNDERSTAND OTHER ASPECTS OF A SENSE. FOR INSTANCE, JUST AS COLOR SHIFTS WITH BRIGHTNESS, THE SMELL OF AN ODOR IS RELATIVE TO ITS INTENSITY. IN FACT, MOST NATURALLY OCCURRING ODORS ARE NOT ONE MOLECULE, BUT MIXTURES OF MANY MOLECULES AT DIFFERENT INTENSITIES. AT THE OLFACTORY RECEPTOR LEVEL, WE KNOW THAT ONE ODORANT MAY INHIBIT ANOTHER LEADING TO A CHANGE IN EACH OTHER’S STRENGTH. KNOWING HOW AND WHAT INTERACTIONS TAKE PLACE IN AN ODOR MIXTURE HAS CLINICAL RELEVANCE. IF WE UNDERSTAND INTERACTIONS IN ODOR MIXTURES, WE COULD SUPPRESS UNAPPETIZING ODORANTS IN MEDICINES THAT LEAD TO LACK OF COMPLIANCE AS WELL AS INCREASE PALATABLE ODORANTS IN INDIVIDUALS WITH PARTIAL LOSS (E.G. ELDERLY). FURTHERMORE, KNOWING MIXTURE INTENSITY WILL SUPPLEMENT FIELDS TRYING TO ACCURATELY MEASURE ODORS (ENVIRONMENTAL REGULATION) OR RECREATE THEM (FOOD SCIENCE). IN THIS PROPOSAL, I WILL COLLECT HIGH-QUALITY, PUBLIC DATA SETS LINKING MOLECULAR STRUCTURE TO PERCEIVED INTENSITY AND BUILD OPEN-ACCESS TOOLS TO PROVIDE PRACTICAL, ACCESSIBLE PREDICTIONS TO ADVANCE THE SCIENTIFIC FIELD.

THE PURPOSE OF THIS AGREEMENT IS TO MONITOR VOLATILE SIGNALS RESULTING FROM VACCINE ADMINISTRATION IN A MODEL MAMMALIAN SYSTEM.

INTERNAL AND EXTERNAL INFLUENCES ON INFANTS' SHORT-TERM FEEDING BEHAVIORS

TO DEVELOP STATE-OF-THE ART TECHNIQUES FOR IDENTIFYING SOURCES OF ODORPRINT VARIATION TO IMPROVE WILDLIFE DISEASE MONITORING AND SURVEILLANCE.

DEVELOPMENT OF TECHNIQUES OR IDENTIFYING CHEMOSENSORY SIGNALS TO SUPPORT HIGH PATHOGENIC H5N1 AVIAN INFLUENZA SURVEILLANCE.

THE PURPOSE OF THIS AGREEMENT IS TO SUPPORT RESEARCH OF CHEMOSENSORY ASPECTS OF WILDLIFE DAMAGE MANAGEMENT.

EVALUATION OF BEHAVIORAL IMPACTS OF VACCINATION PROGRAMS.

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH FOR TRAINING BIOSENSORS TO IDENTIFY POPULATIONS AND/OR INDIVIDUAL BIRDS INFECTED WITH AVIAN INFLUE

THE MOLECULAR BASIS FOR A BROAD RANGE OF PHENOTYPES RELATED TO HTAS2R38

17-7442-1213-CA REVISION NO. 2 EXTENDS TO EXPIRATION DATE TOMARCH 31, 2019, IN ALL OTHER RESPECTS, THE ORIGINAL TERMS SHALL REMAIN IN EFFECT.

BRAIN HEDONIC CIRCUITRY MEDIATING 'LIKING' AND 'WANTING' FOR REWARD - PROJECT SUMMARY/ABSTRACT: NORMAL HEDONIC FUNCTION, OR `LIKING' REACTIONS TO POSITIVE AFFECTIVE EVENTS, IS ESSENTIAL FOR MENTAL HEALTH.1–3 DYSFUNCTION IN HEDONIC BRAIN CIRCUITRY MAY CONTRIBUTE TO MOOD DISORDERS, ADDICTION, AND EATING DISORDERS. 1,4 BRAIN MECHANISMS OF REWARD `LIKING' REMAIN RELATIVELY LESS UNDERSTOOD THAN MECHANISMS OF INCENTIVE MOTIVATION (`WANTING) AND REWARD LEARNING. `LIKING' REACTIONS CAN BE AMPLIFIED BY A NETWORK OF HEDONIC HOTSPOTS, WHICH ARE SMALL SUBREGIONS OF NUCLEUS ACCUMBENS, VENTRAL PALLIDUM, ORBITOFRONTAL CORTEX, AND INSULA THAT ARE UNIQUELY ABLE, WHEN NEUROCHEMICALLY OR OPTOGENETICALLY STIMULATED, TO CAUSALLY INCREASE THE HEDONIC IMPACT OF PALATABLE REWARDS.1,5–10 THE PRIMARY GOAL OF THIS PROPOSAL IS TO ADVANCE UNDERSTANDING OF `LIKING' CIRCUITRY BY INVESTIGATING CIRCUIT-LEVEL FUNCTIONAL INTERACTIONS BETWEEN HEDONIC HOTSPOTS THAT AMPLIFY `LIKING', EXAMINING NEURONAL CODING OF `LIKING' IMPACT WITHIN HEDONIC HOTSPOTS, AND CONSOLIDATING MY DISCOVERY OF A NOVEL HEDONIC HOTSPOT IN ANTERIOR CINGULATE CORTEX. TO DATE I'VE SHOWN THAT OPTOGENETICALLY ACTIVATING HOTSPOTS IN ROSTROMEDIAL ORBITOFRONTAL CORTEX, POSTERIOR VENTRAL PALLIDUM, AND CAUDAL INSULA DOUBLES AFFECTIVE OROFACIAL `LIKING' REACTIONS TO SUCROSE.9,10 CONVERSELY, OPTOGENETICALLY INHIBITING THE VENTRAL PALLIDUM HOTSPOT GENERATES PATHOLOGICALLY INTENSE `DISGUST' REACTIONS TO NORMALLY `LIKED' SWEETNESS.10 USING CELL-SPECIFIC OPTOGENETIC TECHNIQUES IN GAD1-CRE RATS, I'VE FURTHER SHOWN THAT GABAERGIC NEURONS IN THE VENTRAL PALLIDUM HOTSPOT ARE SPECIFICALLY RESPONSIBLE FOR BIDIRECTIONAL CONTROL OF `LIKING' (AIM 1). THE F99 PHASE OF THIS AWARD WILL FURTHER TEST THE HYPOTHESIS THAT MULTIPLE HOTSPOTS ARE UNANIMOUSLY RECRUITED TO CONTROL `LIKING' WHEN ONE HOTSPOT IS STIMULATED (AIM 2C-B), AND WILL CONFIRM MY DISCOVERY OF A NOVEL HEDONIC HOTSPOT IN CAUDAL ANTERIOR CINGULATE CORTEX (AIM 2A). I WILL USE OPTOGENETIC CHR2 STIMULATION TO EXCITE A HOTSPOT AND ANALYZE FOS EXPRESSION PATTERNS IN THE OTHER HOTSPOTS TO CONFIRM RECRUITMENT. FURTHER, USING IN VIVO CALCIUM IMAGING, I WILL CONFIRM RECRUITMENT OF VENTRAL PALLIDUM GABA HOTSPOT NEURONS WHEN THE OFC HOTSPOT IS OPTOGENETICALLY STIMULATED TO GENERATE `LIKING' ENHANCEMENTS. I WILL ALSO TEST THE NECESSITY OF UNANIMOUS RECRUITMENT BY OPTOGENETICALLY STIMULATING ONE HEDONIC HOTSPOT (E.G. OFC) WHILE SIMULTANEOUSLY DISRUPTING THE OTHER (E.G. VP). THE PROPOSED TRAINING WILL FACILITATE MY TRANSITION TO A COMPETITIVE POSTDOCTORAL FELLOWSHIP BY ALLOWING ME TO LEARN IMMUNOHISTOCHEMISTRY, DUAL SITE BRAIN MANIPULATIONS, AND IN-VIVO CALCIUM IMAGING. FOR THE KOO PHASE (AIM3), I WILL IDENTIFY A POSTDOCTORAL LAB ENABLING ME TO INVESTIGATE HOW HOMEOSTATIC CIRCUITRY MODULATES REWARD SYSTEM FUNCTIONS TO INFLUENCE `LIKING' REACTIONS AND `WANTING'. I HAVE PARTICULAR INTEREST IN HOW HEDONIC REWARD SYSTEMS INTERACT WITH REGULATORY HUNGER/SATIETY CIRCUITS IN HYPOTHALAMUS. A F99/K00 AWARD WILL BE INVALUABLE TOWARDS MY TRANSITION TO INDEPENDENCE BY FACILITATING POSTDOCTORAL TRAINING IN MOLECULAR, GENETIC, AND ELECTROPHYSIOLOGICAL TECHNIQUES THAT WILL COMPLEMENT MY CURRENT EXPERTISE IN HEDONIC CIRCUITRY MANIPULATIONS. OVERALL, THIS WORK MAY HELP ELUCIDATE NEURAL MECHANISMS UNDERLYING HEDONIC DYSFUNCTION IN AFFECTIVE DISORDERS.

THE PURPOSE OF THIS AGREEMENT IS TO CHARACTERIZE OLFACTORY PROFILES OF NEW BAIT FORMULATIONS THROUGH INSTRUMENTAL ANALYSES AND TASTE PROFILES VIA BI

THE PURPOSE OF THIS AGREEMENT IS TO COMPARE THE ODOR PROFILES OF INFECTION AND VACCINATION.

I. PURPOSE/OBJECTIVES MANY DISEASES ARE ASSOCIATED WITH DISTINCT BODY ODORS. SEVERAL RESEARCH STUDIES ARISING FROM COLLABORATION BETWEEN NWRC AND MONELL HAVE FOUND THAT BIOSENSOR ANIMALS OR CHEMO

USING MACHINE LEARNING TO PREDICT ODOR CHARACTERISTICS FROM MOLECULAR STRUCTURE

INTERFERONS IN TASTE CELL TURNOVER AND TASTE DISORDERS

UNCOVERING NOVEL ROLES FOR DORSAL ROOT GANGLIA NEURONS IN NUTRIENT SENSING AND FOOD INTAKE CONTROL - PROJECT SUMMARY THE DECISION ON WHEN AND HOW MUCH TO EAT IS FUNDAMENTAL TO AN ANIMAL’S ABILITY TO LIVE, AND REGULATION OF FEEDING BEHAVIOR IS DICTATED BY COMPLEX COMMUNICATIONS BETWEEN THE GUT AND THE BRAIN. RESEARCH ON GUT-BRAIN NEURAL COMMUNICATION FOR THE CONTROL OF FEEDING BEHAVIOR HAS FOCUSED ALMOST EXCLUSIVELY ON SIGNALING VIA THE VAGUS NERVE, THE FIBERS OF WHICH INNERVATE THE GUT VISCERA AND PROJECT TO THE HINDBRAIN TO INFLUENCE KEY BRAIN REGIONS THAT DRIVE HUNGER AND SATIATION. WHILE THE VAGUS NERVE PLAYS A FUNDAMENTAL AND SIGNIFICANT ROLE IN NUTRIENT SENSING, IT IS NOT THE ONLY MECHANISM THROUGH WHICH NUTRITIONAL INFORMATION IS RELAYED TO THE BRAIN. INDEED, PSEUDO-UNIPOLAR NEURONS IN THE DORSAL ROOT GANGLIA (DRG) DIRECTLY INNERVATE THE INTESTINES AND RELAY SENSORY INPUT TO THE SPINAL CORD VIA THE SPLANCHNIC NERVE. HOWEVER, COMPARED TO THE VAGUS, THE ROLE OF SPINAL AFFERENT PATHWAYS IN ENERGY BALANCE CONTROL IS POORLY UNDERSTOOD AND REPRESENTS A MAJOR UNEXPLORED AREA THAT COULD LEAD TO BETTER UNDERSTANDING OF GUT-BRAIN COMMUNICATION. MY SPONSOR LAB (ALHADEFF) RECENTLY DEMONSTRATED THAT BLOCKING SPINAL AFFERENT SIGNALING DECREASES IN VIVO NEURAL ACTIVITY CHANGES ELICITED BY INTESTINAL GLUCOSE IN HYPOTHALAMIC HUNGER NEURONS. FURTHERMORE, OUR PILOT DATA INDICATE THAT DRG NEURONS ARE DOSE-DEPENDENTLY ACTIVATED BY GLUCOSE INFUSED IN TO THE INTESTINE. WHILE THESE DATA REVEAL A SPINAL GUT-BRAIN PATHWAY THAT IS INVOLVED IN GLUCOSE SENSING, THE MECHANISMS THROUGH WHICH SPINAL AFFERENT-MEDIATED NUTRIENT DETECTION OCCUR ARE UNKNOWN, AND THERE IS A CRITICAL GAP IN KNOWLEDGE REGARDING THE CONNECTIVITY BETWEEN THE GUT AND THE DRG. AS THE FIRST NUTRIENT-SENSING SITE IN THE INTESTINE, THE DUODENUM SITS AT A CRITICAL JUNCTION TO SENSE NUTRIENTS AND QUICKLY MODULATE FOOD INTAKE. THEREFORE, THIS PROPOSAL INVESTIGATES THE INVOLVEMENT OF DUODENUM-PROJECTING DRG NEURONS IN INTESTINAL NUTRIENT DETECTION. IN THE FIRST AIM, I WILL USE ANATOMICAL TRACING TO MAP DUODENUM TO DORSAL ROOT GANGLION CONNECTIONS ALONG THE THORACIC AND LUMBAR REGIONS OF THE SPINAL CORD. THE RESULTS FROM THESE EXPERIMENTS WILL PROVIDE IMPORTANT ANATOMICAL GROUNDWORK TO COMPREHENSIVELY CHARACTERIZE NUTRIENT SENSING BY SPINAL AFFERENTS. IN AIM 2, I WILL TEST THE SPECIFICITY WITH WHICH DRG NEURONS RESPOND TO NUTRIENTS. HERE, I WILL USE IN VIVO 2-PHOTON CALCIUM IMAGING OF DRG NEURONS IN RESPONSE TO INFUSIONS OF DIFFERENT NUTRIENTS INTO THE GUT. THE RESULTS OF THESE EXPERIMENTS WILL PROVIDE PRECISE TEMPORAL INFORMATION AND POPULATION DYNAMICS ON HOW DRG NEURONS ARE TUNED TO DETECT SPECIFIC NUTRIENTS. THE COMBINED EXPERTISE OF ALHADEFF (SPONSOR) AND LUO (CO- SPONSOR) LABS, ALONG WITH MY MENTORSHIP COMMITTEE, WILL GIVE ME AMPLE SUPPORT AND EXPERTISE TO ADDRESS THE PROPOSED EXPERIMENTS. THESE COMPLEMENTARY AIMS WILL UNCOVER FUNDAMENTAL ROLES FOR NUTRIENT SENSING BY DRG NEURONS, A NEURAL POPULATION WHICH HAS PREVIOUSLY BEEN UNDERAPPRECIATED FOR ITS CONTRIBUTION TO ENERGY BALANCE AND FEEDING BEHAVIOR.

DEVELOP SCIENTIFIC INFORMATION ON THE CHEMICAL SENSES (I.E. TASTE AND OLFACTION) OF SELECTED WILD VERTEBRATE SPECIES AND PROVIDE FOR INTERCHANGE OF

DEVELOP SCIENTIFIC INFORMATION ON THE CHEMICAL SENSES (I.E. TASTE AND OLFACTION) OF SELECTED WILD VERTEBRATE SPECIES AND PROVIDE FOR INTERCHANGE OF

ANALYSIS OF ALCOHOL-RELATED INGESTIVE BEHAVIOR IN MICE

DEVELOPE SCIENTIFIC INFORMATION ON THE CHEMICAL SENSES (I.E. TASTE AND OLFACTION)OF SELECTED WILD VERTEBRATE SPECIES AND PROVIDE FOR INTERCHANGE OF

CLINICAL AND EVOLUTIONARY SIGNIFICANCE OF THE TASTE AND ORAL DIGESTION OF STARCH

IN THIS STUDY, THE UNDERLYING FUNCTIONAL CAUSES OF CHANGES I VOLATILE PROFILES DUE TO DISEASE CONDITIONS WILL BE ELUCIDATED IN A MOUSE MODEL. THIS INFORMATION WILL BE SIGNIFICANTBECAUSE IT WILL ALL

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH FOR TRAINING BIOSENSORS TO IDENTIFY POPULATIONS AND/OR INDIVIDUAL BIRDS INFECTED WITH AVIAN INFLUE

THE PURPOSE OF THIS AGREEMENT IS TO CHARACTERIZE OLFACTORY PROFILES OF NEW BAIT FORMULATIONS THROUGH INSTRUMENTAL ANALYSES AND TASTE PROFILES VIA BI

UPPER AIRWAY SENSORY IRRITATION AND AERODYNAMIC COUGH ANALYSIS IN RESPONSE TO ODORS AND SENSORY IRRITANTS

EXAMINE ALTERATIONS IN BOTH THE VOLATILE METABOLOME AND GUT MICROBIOME (16S RRNA) PRODUCED BY INFLAMMATION IN MICE.

CONTINUED APPLICATION OF CHEMOSENSORY AN

SALTY TASTE: ASSESSING A STRATEGY TO REDUCE CHILDREN'S PREFERENCE

THE ROLE OF SINGLE OLFACTORY RECEPTORS IN ODOR PERCEPTION

DEVELOPMENT OF A NOVEL APPROACH TO CHARACTERIZE HUMAN CHEMOSENSORY PERCEPTION - PROJECT SUMMARY THE SARS-COV-2 PANDEMIC HAS RAISED PUBLIC AWARENESS OF THE IMPORTANCE OF THE CHEMICAL SENSES, AND HIGHLIGHTED THE NEED FOR BETTER CLINICAL TOOLS TO TEST THEM DUE TO THE SIGNIFICANT UNDERESTIMATION OF CHEMOSENSORY LOSS RELATED TO COVID-19 IN EARLY 2020. THE RECENTLY DEVELOPED MONELL FLAVOR QUIZ (MFQ) DIRECTLY ADDRESSES THESE KEY DEFICIENCIES BY ENABLING COMPREHENSIVE OBJECTIVE MEASUREMENT OF CHEMOSENSATION (SMELL, TASTE, AND CHEMESTHESIS) AND IS AVAILABLE FOR NATIONWIDE DISTRIBUTION. DEVELOPED AS AN ACCESSIBLE TEST, THE MFQ CAN CAPTURE A MORE REPRESENTATIVE SAMPLE—NO LONGER LIMITED BY GEOGRAPHICAL OR LOGISTICAL CONSTRAINTS, IT ENABLES PEOPLE TO MONITOR THEIR TASTE AND SMELL ABILITY IN THE CONVENIENCE OF THEIR OWN HOME. TO ADDRESS THE COMPLEXITY IN CHEMOSENSORY ABILITY, THE MFQ IS DESIGNED TO BRIDGE THE GAP BETWEEN CHANGES IN CHEMOSENSATION AND LIKING TO BETTER UNDERSTAND EFFECTS OF CHEMOSENSORY DYSFUNCTION ON OVERALL DIETARY QUALITY. THIS PROPOSAL AIMS TO (A) DEPLOY THE MFQ TO CHARACTERIZE SUBTYPES OF CHEMOSENSORY DYSFUNCTION (E.G., THOSE SUFFERING FROM CO- OCCURRING CHEMOSENSORY DYSFUNCTION DUE TO COVID-19) AND (B) ASSESS THE RELIABILITY AND VALIDITY OF A SELF-ADMINISTERED MFQ AGAINST STANDARDIZED MEASURES OF CHEMOSENSATION. AIM I WILL ADDRESS CHEMOSENSATION ABILITY IN FOUR SEPARATE COHORTS, DIFFERING IN THEIR CHEMOSENSORY ABILITY (E.G., LOSS OF SMELL OR LOSS OF TASTE), AND LINK CHEMOSENSORY PERCEPTION AND LIKING TO OVERALL DIET HEALTHINESS; THIS INFORMATION CAN AID IN DOWNSTREAM DEVELOPMENT OF TARGETED INTERVENTIONS FOR COMPLEX CHEMOSENSORY DISORDERS. AIM II WILL COMPARE THE RELIABILITY OF THE MFQ ACROSS MODES OF EXECUTION (SELF-ADMINISTERED VS. IN-PERSON), ACROSS TIME (2-WEEK LAPSE), AND VALIDATE IT AGAINST STANDARDIZED MEASURES OF SMELL AND TASTE. DIRECTLY IN ALIGNMENT WITH NIDCD PRIORITY AREA # 1 IN THE TASTE AND SMELL PROGRAM (UNDERSTANDING NORMAL FUNCTION; DEVELOPING TOOLS TO MEASURE TASTE AND SMELL), THE DATA FROM THIS PROJECT WILL LEAD TO AN ADAPTABLE YET COMPREHENSIVE TEST TO CAPTURE COMPLEX VARIATIONS IN TASTE AND SMELL PERCEPTION, AS WELL AS CHEMESTHETIC PERCEPTION. THE CORRESPONDING TRAINING PLAN IN BIOMEDICAL RESEARCH SUPPORTS MY LONG-TERM RESEARCH GOAL TO UNDERSTAND THE UNIQUE INDIVIDUAL CHEMOSENSORY EXPERIENCE AND HOW IT AFFECTS THE PERCEPTION OF FOOD AND CONTRIBUTES TO QUALITY OF LIFE.

DEVELOP SCIENTIFIC INFORMATION ON THE CHEMICAL SENSES (I.E. TASTE AND OLFACTION) OF SELECTED WILD VERTEBRATE SPECIES AND PROVIDE FOR INTERCHANGE OF

DEVELOPE SCIENTIFIC INFORMATION ON THE CHEMICAL SENSES (I.E. TASTE AND OLFACTION)OF SELECTED WILD VERTEBRATE SPECIES AND PROVIDE FOR INTERCHANGE OF

TOWARDS UNIVERSAL CHEMOSENSORY TESTING - PROJECT SUMMARY THE COVID-19 PANDEMIC HAS BROUGHT SMELL AND TASTE DYSFUNCTION TO MAINSTREAM ATTENTION. DESPITE ITS ROLE IN SIGNALING DISEASE, AS WELL AS SAFETY, ATTACHMENT, AND QUALITY OF LIFE, THE DIAGNOSIS OF CHEMOSENSORY DISORDERS IS FAR FROM ACCESSIBLE FOR MOST PATIENTS OR ROUTINELY EMPLOYED BY MOST HEALTH CARE PROVIDERS. ALIGNED WITH THE GOALS OF THE 2022-2027 DRAFT OF THE NIDCD STRATEGIC PLAN, WE PROPOSE A CONFERENCE TO BRING TOGETHER SCIENTISTS, CLINICIANS, PUBLIC HEALTH OFFICIALS, PATIENTS AND ALL OTHER INTERESTED PARTIES TO IDENTIFY OPPORTUNITIES AND CHALLENGES FOR IMPLEMENTING ROUTINE CHEMOSENSORY TESTING NATIONWIDE. THE ORGANIZATION AND EXECUTION OF THE CONFERENCE RESULT FROM A COLLABORATIVE EFFORT OF FOUR LEADERS WITH DIVERSE BACKGROUNDS IN THE SCIENCE AND CLINICAL APPLICATION OF CHEMOSENSORY TESTING WHO REPRESENT INSTITUTIONS WITH DISTINCT EXPERTISE IN THESE AREAS. PARTICIPANTS IN THIS CONFERENCE WILL (I) SHARE STATE-OF-THE-ART METHODS IN CHEMOSENSORY TESTING; (II) IDENTIFY BENEFITS AND PRACTICALITIES OF CHEMOSENSORY SCREENING BOTH FOR INDIVIDUALS AND AT THE POPULATION LEVEL; (III) COMMUNICATE THIS INFORMATION TO MEDICAL ASSOCIATIONS, HEALTH CARE PROFESSIONALS, ACADEMIC INSTITUTIONS, GOVERNMENTAL AGENCIES, INSURANCE COMPANIES, INDUSTRY, AND THE GENERAL PUBLIC; AND (IV) PRODUCE A PEER- REVIEWED, CONSENSUS WHITE PAPER FOR UNIVERSAL CHEMOSENSORY TESTING DETAILING THE RATIONALE AND RECOMMENDATIONS THAT EMERGE FROM THE CONFERENCE, INCLUDING A STRATEGY TO PRODUCE GUIDELINES MODELED ON OTHER SUCCESSFUL CAMPAIGNS. THIS IN-PERSON CONFERENCE WILL INCLUDE VIRTUAL COMPONENTS AND CHILDCARE ASSISTANCE, THUS ENABLING THE WIDER PARTICIPATION OF DIVERSE GROUPS. WE WILL ALSO MAKE VIDEOS OF THE PRESENTATIONS AVAILABLE ONLINE AND GENERATE PLAIN LANGUAGE MATERIALS FOR THE LAY PUBLIC, WITH BOTH SPANISH AND ENGLISH, AS OUTREACH CONTENT. TOGETHER, THESE ACTIVITIES WILL ADVANCE THE USE OF CHEMOSENSORY TESTING IN MULTIPLE CONTEXTS, TO SPEED DIAGNOSIS OF CHEMOSENSORY DISORDERS AND ASSOCIATED HEALTH PROBLEMS, FACILITATE THERAPEUTIC AND SUPPORTIVE INTERVENTIONS FOR AFFECTED INDIVIDUALS, AND IMPROVE HUMAN HEALTH AND QUALITY OF LIFE.

EMERGING STRATEGIES FOR TREATING CHEMOSENSORY DISORDERS

DEVELOPMENT AND VALIDATION OF A RAPID TEST FOR INDIVIDUAL DIFFERENCES IN SWEET LIKING - PROJECT SUMMARY OVERCONSUMPTION OF SUGAR IS ASSOCIATED WITH OBESITY AND RELATED CHRONIC DISEASE, WHICH IN TURN COST ~300,000 LIVES AND ~$546 BILLION ANNUALLY IN THE UNITED STATES ALONE. LEADING HEALTH AGENCIES RECOMMEND REDUCING INTAKE OF ADDED SUGARS, BUT PLEASURE (HEDONICS) FROM SWEETNESS MAY HINDER THE EFFORT TO ACHIEVE THIS GOAL. PEOPLE MIGHT ACCLIMATE TO REDUCED SUGAR IN THE FOOD SUPPLY OVER TIME, ANALOGOUS TO SHIFTS TOWARD PREFERENCE FOR LOWER LEVELS OF SALT THAT OCCUR AFTER REDUCING SODIUM INTAKE, BUT THIS HYPOTHESIS REMAINS UNTESTED. BECAUSE HEDONIC RESPONSE DRIVES CONSUMPTION, COLLECTING LARGE-SCALE DATA TO UNDERSTAND INDIVIDUAL DIFFERENCES IN SWEET HEDONICS ON A POPULATION LEVEL IS A CRITICAL STEP IN GUIDING PUBLIC POLICY. TO FACILITATE POPULATION-BASED STUDIES, I WILL FIRST DETERMINE WHETHER TWO WIDELY USED BUT TIME- AND LABOR-INTENSIVE PSYCHOPHYSICAL SENSORY TESTS DO IN FACT MEASURE THE SAME INDIVIDUAL DIFFERENCES IN SWEET HEDONICS (SUB-AIM 1). ONE TEST ASKS PARTICIPANTS TO COMPARE PAIRS OF SUGAR SOLUTIONS THAT DIFFER IN CONCENTRATION AND DECIDE WHICH SOLUTION THEY PREFER. THE OTHER TEST IS BASED ON SUBJECTIVE RATINGS OF LIKING FOR SUGAR SOLUTIONS OF VARYING CONCENTRATIONS. PARTICIPANTS WILL BE A REPRESENTATIVE SAMPLE OF HEALTHY, US ADULTS (N = 111). THE DATA WILL NOT ONLY DETERMINE AGREEMENT BETWEEN THE TWO APPROACHES TO MEASURE INDIVIDUAL SWEET HEDONIC PATTERNS BUT ALSO WILL BE USED TO EVALUATE SEVERAL BRIEF TESTS (POTENTIAL PROXIES FOR THE MORE TIME-CONSUMING TESTS), INCLUDING THE SIMPLE SWEET TEST, AS CANDIDATES FOR USE IN THE FIELD OR IN PARTICIPANTS’ HOMES TO FACILITATE LARGE-SCALE STUDIES (SUB-AIM 2). FOR EXAMPLE, A BRIEFER, VALID TEST WILL FACILITATE DATA COLLECTION TO EXAMINE POPULATION-LEVEL SHIFTS IN SWEET HEDONIC RESPONSE ACCOMPANYING GENERAL REDUCTIONS IN SUGAR IN PROCESSED FOODS AND SWEETENED BEVERAGES. IN ADDITION, I WILL EXPLORE THE RELATIONSHIP BETWEEN SWEET HEDONIC RESPONSE AND OVERALL DIET QUALITY, ESPECIALLY SUGAR CONSUMPTION (EXPLORATORY AIM). THE PROPOSED WORK WILL ADVANCE OUR CONCEPTUAL UNDERSTANDING OF MEASUREMENT OF SWEET HEDONIC RESPONSE BY CONFIRMING THAT COMMON TESTS MEASURE A SINGLE UNDERLYING TRAIT. FURTHERMORE, IT WILL EXPLORE THE RELATIONSHIP BETWEEN SWEET HEDONICS AND DIET QUALITY USING METHODS ROBUST AGAINST MISREPORTING. MY STUDY WILL ALSO FACILITATE COLLECTION OF DATA ON HEDONIC RESPONSE BY VALIDATING MORE EFFICIENT TESTS, THEREBY SUPPORTING THE NIDCD GOAL OF DEVELOPING TOOLS TO MEASURE TASTE AND SMELL FUNCTION. AS A POSTDOCTORAL TRAINEE, THIS PROJECT WILL PROVIDE ME WITH THE FOUNDATION IN THE THEORY AND PRACTICE OF MEASURING HEDONIC RESPONSE, A SKILL SET THAT CAN BE APPLIED TO OTHER NUTRIENTS OF CONCERN FOR OBESITY AND PUBLIC HEALTH, INCLUDING SALT AND FAT. THESE SKILLS WILL COMPLEMENT MY EXPERTISE IN NUTRITION SCIENCE AND PREPARE ME TO BECOME A LEADING RESEARCHER IN THE FIELD OF SENSORY NUTRITION, WITH THE LONG-TERM GOAL OF FACILITATING PUBLIC HEALTH THROUGH ENHANCED UNDERSTANDING OF HOW DIET AND PERCEPTION INTERACT TO DRIVE FOOD CHOICE.

THE OBJECTIVE OF THIS COOPERATIVE RESEARCH IS TO IDENTIFY AN TEST ELECTRONIC SENSORS FOR DETECTION OF AVIAN INFLUENZA INFECTION IN BIRDS AND THE ENVIRONMENT. THE PRODUCTS OF THIS COOPERATIVE AGREEMEN