Msc Inc

ABERRANT SIGNALING IN B-1 CELLS

PRIMARY CARE TRAINING AND ENHANCEMENT - RESIDENCY TRAINING IN MENTAL AND BEHAVIORAL HEALTH

HUMAN B1-LIKE CELLS AND PNEUMOCOCCAL DEFENSE IN THE ELDERLY

THE DEVELOPMENTAL PATHWAY OF FETAL-DERIVED B CELLS - ABSTRACT STEM CELL THEORY STATES THAT ALL THE BLOOD CELLS ARE DERIVED FROM HEMATOPOIETIC STEM CELLS (HSCS) AND IS A CENTRAL CONCEPT OF HEMATOLOGY AND IMMUNOLOGY. BONE MARROW TRANSPLANT THERAPY FOR BLOOD DISORDERS IS ROOTED IN THE CONCEPT THAT DONOR HSCS CAN REPLACE ALL BLOOD CELLS IN THE RECIPIENT'S BODY. HOWEVER, RECENT RESEARCH HAS CHALLENGED THE STEM CELL THEORY BY SHOWING THAT SOME TISSUE-RESIDENT IMMUNE CELLS DEVELOP FROM ENDOTHELIAL CELLS (EC) OF THE EMBRYO IN AN HSC-INDEPENDENT MANNER AND THESE IMMUNE CELLS MAY NOT BE REPLACED BY HSCS. FURTHERMORE, IT HAS BEEN REPORTED THAT A SIGNIFICANT PERCENTAGE OF CONVENTIONAL B CELLS (B-2 CELLS) ALSO ORIGINATE FROM FETAL EC PROGENITORS IN THE EMBRYO AND PERSIST INTO OLD MICE. THESE STRIKING RESULTS HIGHLIGHT A HUGE KNOWLEDGE GAP IN THE HEMATOLOGY AND IMMUNOLOGY FIELDS BECAUSE HSC-INDEPENDENT B-2 CELL DEVELOPMENT HAS YET TO BE RECOGNIZED. SINCE B CELLS PLAY IMPORTANT ROLES IN PROTECTING AGAINST INFECTIONS AND IN THE PATHOLOGY OF AUTOIMMUNE AND OTHER DISEASES, IT IS CRITICALLY IMPORTANT TO UNDERSTAND THE DEVELOPMENTAL PATHWAYS OF HSC- INDEPENDENT B-CELLS AND THEIR FUNCTIONS COMPARED TO HSC-DERIVED COUNTERPARTS. HOWEVER, IT IS CHALLENGING TO CLARIFY THE ORIGINS OF THESE B-CELLS SINCE THERE ARE MULTIPLE WAVES OF HEMATOPOIESIS FROM ECS IN THE EMBRYO, IN WHICH HSCS AND HSC-INDEPENDENT BLOOD PROGENITORS SEEM TO BE PRODUCED SIMULTANEOUSLY. OUR PRELIMINARY DATA AND OTHER STUDIES SUGGEST THAT THERE ARE AT LEAST THREE WAVES OF B-CELL DEVELOPMENT; 1) INNATE-IMMUNE B-1 CELL DEVELOPMENT, 2) COMMON PROGENITORS FOR INNATE B-1 AND CONVENTIONAL B-2 CELLS, AND 3) B-2 DOMINANT PROGENITORS DERIVED FROM HSCS. OUR OBJECTIVE IS TO DETERMINE THE FUNCTIONAL DIFFERENCES OF B-CELLS BASED ON THEIR ORIGINS AND TO ESTABLISH A REVISED B-CELL DEVELOPMENT MAP FROM EMBRYO TO ADULT, USING COMBINATIONS OF VARIOUS LINEAGE TRACING AND IN VIVO BARCODING MOUSE MODELS. TO PURSUE THESE GOALS, AIM 1 WILL UTILIZE HSC-LABELING MICE (100% LABELING OF HSCS IS ACHIEVED) AND THE HSC-DERIVED LYMPHOID CELL DEPLETION MODEL SO THAT HSC-INDEPENDENT AND DEPENDENT B-CELL SUBSETS WILL BE SEPARATED. THEN, THESE HSC-INDEPENDENT AND DEPENDENT B-CELL SUBSETS WILL BE SORTED AND EXAMINED FOR 1) ANTIBODY AND CYTOKINE SECRETION, CLASS SWITCHING UPON IN VITRO STIMULATION, AND THEIR IGM REPERTOIRE, 2) IN VIVO REPSONSE TO S. PNEUMONIAE INFECTION, AND 3) RESPONSE TO PNEUMOCOCCAL VACCINATION. IN AIM 2, PRELIMINARY DATA IDENTIFIED THE EARLIEST INNATE-IMMUNE RESTRICTED B-PROGENITORS IN THE EARLY FETAL LIVER. ALSO, SCRNA-SEQUENCING OF THE NEONATAL SPLEEN REVEALED THREE SEPARATE B-PROGENITOR CLUSTERS, SUPPORTING OUR HYPOTHESIS. THUS, THE EC-LINEAGE TRACING MOUSE MODEL THAT CAN MARK HSC-INDEPENDENT BLOOD PROGENITORS WILL BE COMBINED WITH IN VIVO BARCODING, WHICH WILL ENABLE VISUALIZATION OF THE CLONAL RELATIONSHIPS BETWEEN HSCS AND FETAL- AND HSC-DERIVED B-PROGENITORS. THE RESULTS OBTAINED FROM THIS PROPOSAL WILL REVISE THE CURRENT PARADIGM OF B-CELL DEVELOPMENT AND WILL BE UTILIZED TO UNDERSTAND PATHOLOGY NOT PREVIOUSLY RECOGNIZED IN THE ABSENCE OF RECOGNIZING THE EXISTANCE OF VARIOUS FETAL-DERIVED B CELL SUBSETS.

AMERICAN RESCUE PLAN ACT FUNDING FOR LOOK-ALIKES

THE ROLE OF BIOLOGICAL SEX IN THE SELF-RENEWAL OF B1 CELLS INTO OLD AGE IN MICE AND HUMANS - PROJECT SUMMARY/ABSTRACT BY THE YEAR 2050 THE WHO PREDICTS THERE WILL BE 2 BILLION PEOPLE AGED 60 YEARS AND OVER. AS THE POPULATION OF AGED INDIVIDUALS RISES SO WILL AGING-ASSOCIATED DISEASES. TO CREATE BETTER PREVENTION STRATEGIES FOR DISEASES IN THE ELDERLY, WE NEED TO ADDRESS FUNDAMENTAL BIOLOGICAL QUESTIONS REGARDING IMMUNE SYSTEM DETERIORATION DURING THE AGING PROCESS. SPECIFICALLY, THE GOAL OF THIS PROPOSAL IS TO DETERMINE WHETHER DEFECTS IN NATURAL IMMUNITY IN THE AGED ARE DUE TO CHANGES IN SELF-RENEWAL OF A SUBSET OF B CELLS, B1 CELLS, WHICH PRODUCE NATURAL ANTIBODIES (NABS). NABS ARE GENERATED IN THE ABSENCE B1 CELL STIMULATION AND CONSTITUTE A KEY MODALITY OF SEROLOGICAL IMMUNITY PROVIDING MANY ESSENTIAL FUNCTIONS WITHIN IN IMMUNE SYSTEM. THE EFFECTIVENESS OF NABS IS ATTRIBUTED TO THEIR DISTINCT GERMLINE-LIKE PROPERTIES THAT RESULT FROM DEVELOPMENT OF B1 CELLS DURING FETAL LIFE WITH PERSISTENCE INTO ADULTHOOD. OUR STUDIES DEMONSTRATE NABS ARE LESS EFFECTIVE AT PROVIDING PROTECTION IN AGED MALES YET, PROTECTION IS MAINTAINED IN AGED FEMALES. IF EFFECTIVE NABS ARE MAINTAINED OVER A LIFETIME, THESE ESSENTIAL PROTEINS COULD AID IN PRODUCING AN INCREASE IN BOTH HEALTH-SPAN AND LIFESPAN; YET IT IS UNKNOWN HOW PROTECTIVE NABS ARE MAINTAINED IN AGED FEMALES BUT NOT AGED MALES. THIS LOSS IN NAB PROTECTION AGAINST INFECTION IN AGED MALES IS NOT ACCOUNTED FOR BY A CHANGE IN THE AMOUNT OF ANTIGEN SPECIFIC ANTIBODY, BUT INSTEAD, IS DUE TO THE LOSS OF ANTIBODY GERMLINE-LIKE FEATURES, WHICH DOES NOT OCCUR IN AGED FEMALES, WHERE B1 CELL DERIVED ANTIBODY REMAINS GERMLINE-LIKE. OUR PRELIMINARY AND PUBLISHED RESULTS SUGGEST THESE FINDINGS ARE A RESULT OF BETTER PERSISTENCE OF B1 CELLS THAT ORIGINATE IN FETAL LIFE WITH ADVANCING AGE IN FEMALES AS OPPOSED TO MALES. THE REASON FOR THIS IS UNKNOWN BUT IT IS SPECULATED THAT B1 CELL SELF-RENEWAL IS RESPONSIBLE. WE HYPOTHESIZE AGE AND SEX-ASSOCIATED DEFECTS IN THE PROTECTIVE CAPACITY OF NATURAL IGM RESULTS FROM LOSS OF ADULT B1 CELL SELF-RENEWAL IN AGED MALES BUT NOT AGED FEMALES. TO TEST THIS HYPOTHESIS, WE WILL UTILIZE ADVANCED GENETIC TECHNIQUES THAT PROVIDE THE MEANS FOR THE FIRST TIME TO SEPARATELY TRACK B1 CELLS ORIGINATING IN FETAL LIFE FROM THOSE ARISING IN ADULT LIFE, AND FOR THE FIRST TIME TO MEASURE THE STAGE AT WHICH B1 CELLS ARE IN CELL CYCLE, ACCORDING TO SEX AND AGE. WE WILL 1) DETERMINE HOW BIOLOGICAL SEX INFLUENCES LONG TERM PERSISTENCE OF MOUSE B1 CELLS GENERATED DURING DIFFERENT PHASES OF LIFE; 2) EXAMINE SEX SPECIFIC REGULATION OF MOUSE B1 CELL CYCLE PROGRESSION AND SELF-RENEWAL WITH INCREASING AGE; AND 3) EVALUATE THE ROLE OF SEX IN SPECIFYING HUMAN B1 CELL CYCLE DYNAMICS AND HUMAN B1 CELL NATURAL ANTIBODY FUNCTION. THIS PROJECT WILL ELUCIDATE MECHANISMS OF DIFFERENTIAL B1 CELL SELF-RENEWAL IN AGED MALES AND FEMALES, WHICH WILL PROVIDE CRITICAL INFORMATION FOR DESIGNING NOVEL APPROACHES TO MAINTAIN HEALTHY NATURAL IMMUNITY INTO OLD AGE BY FAVORING SELF - RENEWAL OF EARLY APPEARING B1 CELLS.

SEX DETERMINES AGE-RELATED CHANGES IN THE REPERTOIRE AND FUNCTION OF NATURAL ANTIBODIES PROTECTIVE AGAINST STREPTOCOCCUS PNEUMONIAE WITH INCREASING AGE

COUNTER CBRN TERRORISM TRAINING

AUGMENTING THE ON-SCENE MEDIC (ATOM): DEVELOPMENT OF A HEAD-MOUNTED DISPLAY APPLICATION TO REDUCE PREHOSPITAL PEDIATRIC MEDICATION ERRORS - PROJECT SUMMARY THE OBJECTIVE OF THIS PROJECT IS TO DEVELOP A SAFE AND EFFECTIVE DYNAMIC COGNITIVE AID APPLICATION FOR USE THROUGH A HEAD-MOUNTED DISPLAY (HMD), TO REDUCE ERROR RATES ASSOCIATED WITH PEDIATRIC MEDICATION ADMINISTRATION (PMA) BY EMERGENCY MEDICAL SERVICES (EMS). THIS OBJECTIVE WILL BE ACHIEVED BY EXAMINING CHARACTERISTICS ASSOCIATED WITH PMA, USING A DESIGN THINKING PROCESS TO DEVELOP A PROTOTYPE APPLICATION, EXAMINING USABILITY OF THE PROTOTYPE, AND TESTING THE SAFETY AND EFFICACY IN A RANDOMIZED CONTROLLED TRIAL. ERRORS ASSOCIATED WITH PMA IN EMS ARE ALARMINGLY HIGH. NUMEROUS STUDIES HAVE SHOWN THAT THERE IS A 31% ERROR RATE ACROSS ALL DRUGS ADMINISTERED TO CHILDREN BY EMS. MEDICATIONS SUCH AS MIDAZOLAM AND FENTANYL HAVE EVEN HIGHER RATES AT 61% AND 65%, RESPECTFULLY, WITH MANY BEING 10-FOLD ERRORS. SADLY, PREVIOUS STRATEGIES HAVE HAD LITTLE IMPACT ON REDUCING ERROR RATES BELOW 31%. SYSTEM CHANGES HAVE FAILED DUE TO INCONSISTENCIES IN EMS SYSTEMS, AND CHALLENGES ASSOCIATED WITH MEDICATION SHORTAGES. PREVIOUSLY DEVELOPED COGNITIVE AIDS HAVE FALLEN SHORT OFTEN DUE TO THE FACT THEY GENERALLY ACT AS SIMPLE REFERENCE TOOLS AND DO NOT ADDRESS ALL CAUSES OF ERROR ASSOCIATED WITH PMA. AS A RESULT, WE ARE PROPOSING THE MOST COMPREHENSIVE DESIGN PROCESS EVER TAKEN TO COMBAT THIS ISSUE, UTILIZING ADVANCED TECHNOLOGY, TO IMPLEMENT A DYNAMIC COGNITIVE AID TO HELP PROVIDERS IMPROVE DOSING ACCURACY DURING PMA. WE HYPOTHESIZE THAT PMA ERRORS IN EMS WILL BE SIGNIFICANTLY REDUCED BY THIS APPLICATION DUE TO THE COMPREHENSIVE AND RIGOROUS DESIGN THINKING PROCESS WE WILL UTILIZE FOLLOWED BY A RANDOMIZED CONTROLLED TRIAL TO TEST SAFETY AND EFFICACY. OUR INTERDISCIPLINARY TEAM WILL COMBINE THE FIELDS OF PEDIATRIC EMERGENCY MEDICINE, EMS, ENGINEERING, COMPUTER SCIENCE AND USER INTERFACE/USER EXPERIENCE TO ADDRESS THIS ISSUE WITH THE SUPPORT AND EFFORT OF TWO MEDICAL SCHOOLS IN MICHIGAN. IN SA1 WE WILL DEVELOP A PROTOTYPE APPLICATION. THIS WILL BEGIN WITH IDENTIFYING USER AND CONTEXTUAL INFORMATION ASSOCIATED WITH PMA, AND EXAMINE FAILURE MODES, ROOT CAUSES, AND A TASK ANALYSIS OF THE PROCEDURE. WE WILL THEN PROCEED INTO A COMPREHENSIVE DESIGN THINKING PROCESS TO DEVELOP THE APPLICATION. DURING THIS PROCESS WE WILL ALSO CREATE A DESKTOP PROGRAM THAT WILL ALLOW EMS AGENCY ADMINISTRATORS TO ADD NEW MEDICATIONS TO THE HMD APPLICATION. IN SA2, WE WILL EXAMINE USABILITY OF THE HMD APPLICATION AND ASSOCIATED DESKTOP PROGRAM IN A SIMULATION-BASED ENVIRONMENT WITH A SAMPLE OF END USERS, EXAMINING TASK DURATION, COGNITIVE LOAD AND ERROR RATES AND MAKE ANY NECESSARY REFINEMENTS. IN SA3, WE WILL TEST THE HMD APPLICATION IN A SIMULATION-BASED RANDOMIZED CONTROLLED TRIAL TO EXAMINE ITS SAFETY AND EFFICACY FOR USE IN EMS. THIS WILL RESULT IN A SAFE AND EFFECTIVE TOOL TO MITIGATE THIS ALARMING ISSUE IN THE VULNERABLE EMS PEDIATRIC POPULATION.

TO ADDRESS THE PRESSING FINANCIAL NEED STUDENTS AT HIGHER EDUCATION SCHOOLS DUE TO THE DISRUPTION OF CAMPUS OPERATIONS FROM THE CORONAVIRUS PANDEMIC.

EMSC TARGETED ISSUE GRANTS

PORT SECURITY GRANT PROGRAM

DURABLE VISIBLE LIGHT-ACTIVATED ANTIVRAL COATINGS FOR FABRICS USED FOR PERSONAL P

EMSC TARGETED ISSUE GRANTS

CARES ACT GRANT TO STUDENTS IN NEED

CARES ACT GRANT FOR SCHOOL IN NEED

THIS AGREEMENT WILL PROVIDE FUNDING TO MSC REALTY TO CLEAN UP A BROWNFIELDS SITES ALONG EDDY STREET IN PROVIDENCE, RHODE ISLAND. BROWNFIELDS ARE REAL PROPERTY, THE EXPANSION, DEVELOPMENT OR REUSE OF WHICH MAY BE COMPLICATED BY THE PRESENCE OR POTENTIAL PRESENCE OF A HAZARDOUS SUBSTANCE, POLLUTANT, OR CONTAMINANT.

CARES ACT RLF

PORT SECURITY GRANT PROGRAM

ASSISTANCE TO FIREFIGHTERS GRANTS

TAU-BINDING B CELLS IN ALZHEIMER'S DISEASE

DIFFERENT ROLES OF FETAL- AND ADULT-DERIVED IGA SECRETING CELLS AGAINST GI INFECTION - ABSTRACT IGA IS THE MOST ABUNDANT IMMUNOGLOBULIN PRODUCED IN THE LAMINA PROPRIA (LP) OF THE INTESTINE AND PROTECTS THE HOST AGAINST MICROBIAL INVASIONS INTO INTESTINAL MUCOSA BY COATING AND EXCLUDING THEM. SELECTIVE IGA DEFICIENCY IS THE MOST COMMON IMMUNODEFICIENCY, AND MORE THAN 50% OF PATIENTS ARE ASYMPTOMATIC. HOWEVER, OTHER PATIENTS DEVELOP VARIOUS DISEASES SUCH AS INFLAMMATORY BOWEL DISEASES, ALLERGIES, AUTOIMMUNE DISEASES, AND RECURRENT INFECTIONS. DESPITE THE ESSENTIAL ROLES OF IGA, IT STILL REMAINS UNKNOWN WHAT CAUSES THE DIFFERENT CLINICAL MANIFESTATIONS OF THIS DISEASE. ONE OF THE BARRIERS TO UNDERSTANDING THE PATHOLOGY OF SELECTIVE IGA DEFICIENCY IS A GAP OF KNOWLEDGE ABOUT THE HETEROGENEITY OF DEVELOPMENTAL ORIGIN OF THE IGA-SECRETING CELLS. OUR LONG-TERM GOAL IS TO FILL THIS KNOWLEDGE GAP AND TO DETERMINE THE ROLES OF IGA+ CELLS OF DIFFERENT ORIGINS IN THE MUCOSAL IMMUNITY. THERE ARE TWO KNOWN PATHWAYS IN PRODUCING IGA SECRETING CELLS: T-CELL INDEPENDENT (TI) AND T-CELL DEPENDENT (TD) PATHWAYS. TI-IGA IS A LOW-AFFINITY POLYCLONAL ANTIBODY THAT COATS BACTERIA AND MAINTAINS THE MICROBIOME HOMEOSTASIS, WHILE TD-IGA UNDERGOES SOMATIC HYPERMUTATION AND REACTS AGAINST SPECIFIC ANTIGENS. THE PRECURSORS OF THESE TI- AND TD-IGA HAVE BEEN CONTROVERSIAL, BUT IT HAS RECENTLY BEEN DEMONSTRATED THAT TI IGA+ CELLS ARE DERIVED FROM PERITONEAL B-1B CELLS WHILE TD IGA+ CELLS ARE FROM GERMINAL CENTER B-2 CELLS. IT IS GENERALLY CONSIDERED THAT THESE B-1B AND B-2 CELLS ARE ULTIMATELY PRODUCED BY HEMATOPOIETIC STEM CELLS (HSCS) THAT RESIDE IN THE BONE MARROW (BM). HOWEVER, OUR AND OTHERS' PRIOR WORK HAS SHOWN THAT B-1B CELLS ARE ALSO PRODUCED BY HSC-INDEPENDENT FETAL PROGENITORS DURING EMBRYONIC DEVELOPMENT. OUR LINEAGE TRACING DATA INDICATED THAT IGA+ CELLS IN THE LAMINA PROPRIA (LP) ARE DERIVED FROM EMBRYONIC DAY (E) 7.5 ENDOTHELIAL CELLS (ECS), THREE DAYS BEFORE THE FIRST HSC PRODUCTION IN THE EMBRYO. OUR LINEAGE TRACING SYSTEM USING EC-DERIVED (CDH5CREERT2) AND HSC- DERIVED (FGD5CREERT2) ENABLES US TO SEGREGATE IGA+ CELLS IN THE LP OF DIFFERENT ORIGINS. THUS, THE CENTRAL HYPOTHESIS OF THIS PROJECT IS THAT IGA+ CELLS IN THE LP CONSISTS OF CELLS WITH DIFFERENT ORIGINS: FETAL (EC)- AND HSC- DERIVED AND THAT IGA+ CELLS OF DIFFERENT ORIGINS HAVE DIFFERENT ROLES AGAINST GUT INJURY AND INFECTIONS. TO TEST OUR HYPOTHESIS, IN AIM1, WE WILL EXAMINE TI- AND TD- CLASS SWITCHING OF FETAL- AND HSC-DERIVED B CELLS. WE WILL ALSO VISUALIZE THESE FETAL- AND HSC-DERIVED TI- AND TD- IGA+ CELLS USING SCRNA-SEQUENCING AND BCR REPERTOIRE- SEQUENCING AND WILL DISPLAY THE MOLECULAR DIFFERENCES OF THESE CELLS. IN AIM 2, WE WILL EXAMINE THE PROTECTIVE ROLES OF FETAL- AND HSC-DERIVED IGA+ CELLS AGAINST GI INFECTION WITH C. RODENTIUM. THE RESULTS OBTAINED FROM THIS PROPOSAL WILL ESTABLISH A NEW PARADIGM OF THE DEVELOPMENTAL ORIGIN OF IGA+ CELLS AND THEIR FUNCTIONS IN THE GUT HOMEOSTASIS AND INFECTIONS.

HIGHER EDUCATION EMERGENCY RELIEF FUND - FIPSE

INTERMINGLING OF CIRCULATING B CELLS AND CEREBRAL SPINAL FLUID B CELLS WITH ADVANCING AGE - THE BROAD, LONG TERM OBJECTIVE OF THIS PROJECT IS TO ELUCIDATE THE ROLE THAT THE B CELL ARM OF THE IMMUNE SYSTEM PLAYS IN THE PATHOPHYSIOLOGY OF AGING FROM THE STAND-POINT OF, AND HYPOTHESIS THAT, B CELLS AND THE ANTIBODIES THEY MAKE PLAY A PATHOGENIC ROLE. THE SPECIFIC FOCUS OF THE PRESENT APPLICATION IS TO ELUCIDATE THE IMMUNOGLOBULIN REPERTOIRE OF B CELLS PRESENT IN HUMAN CEREBRAL SPINAL FLUID (CSF) SAMPLES IN COMPARISON WITH B CELLS CIRCULATING IN THE PERIPHERY TO DETERMINE THE EXTENT TO WHICH THERE IS B CELL INTERMINGLING BETWEEN THE PERIPHERY AND THE CENTRAL NERVOUS SYSTEM (CNS) IN OLD AGE. THIS WORK IS DESIGNED TO TEST A NOVEL AND UNEXPLORED MECHANISM UNDERLYING THE DYSCRASIAS OF AGING AND ASSOCIATED NEURODEGENERATION. B CELLS EXIST IN THE CNS OF HEALTHY PEOPLE AS EVIDENCED BY THEIR PRESENCE IN CEREBRAL SPINAL FLUID (CSF). WHERE DO THESE B CELLS COME FROM AND HOW DO THEY END UP IN THE CNS? B CELLS IN THE PERIPHERY CIRCULATE THROUGHOUT THE BODY BUT ONE PLACE THEY DO NOT ENTER IS THE CENTRAL NERVOUS SYSTEM (PROTECTED BY THE BLOOD BRAIN BARRIER). OR DO THEY? WE ADDRESSED THIS ISSUE BY ANALYZING ANTIBODIES PRODUCED BY INDIVIDUAL B CELLS, BECAUSE ANTIBODY SEQUENCE CAN ACT AS AN ADDRESS OR IDENTIFIER FOR EACH B CELL. WE FOUND THAT CNS B CELLS CONSTITUTE A POPULATION SEPARATE AND DISTINCT FROM PERIPHERAL B CELLS IN HEALTHY YOUNG HUMAN VOLUNTEERS. A RECENT STUDY OF YOUNG MICE BY ANOTHER GROUP CONFIRMED THAT CNS B CELLS ARE COMPLETELY SEPARATE AND DISTINCT FROM PERIPHERAL B CELLS IN THESE ANIMALS…BUT, OF GREATER CONSEQUENCE, THE SAME STUDY REPORTED THAT IN OLD MICE, THE ANTIBODY REPERTOIRES OF CNS AND PERIPHERAL B CELLS OVERLAPPED TO A SIGNIFICANT EXTENT, INDICATING TRANSLOCATION/MIGRATION OF PERIPHERAL B CELLS TO THE CNS. IT IS NOW IMPERATIVE TO DETERMINE WHETHER THE SAME OCCURS IN OLD PEOPLE, AS THIS COULD CONSTITUTE A MECHANISM WHEREBY AUTOREACTIVE B CELLS GAIN ACCESS TO THE CNS AND PROMOTE INFLAMMATION, WHICH IS CONSIDERED AN IMPORTANT FACTOR IN COGNITIVE AGING AND THE PATHOGENESIS OF NEURODEGENERATIVE ILLNESS. THE UNKNOWN DEGREE TO WHICH PERIPHERAL B CELLS CONTRIBUTE TO THE POPULATION OF CNS B CELLS IN OLD PEOPLE REPRESENTS A KEY GAP IN KNOWLEDGE WHOSE RESOLUTION IS LIKELY TO HAVE IMPORTANT IMPLICATIONS FOR CONCEPTS REGARDING NORMAL PHYSIOLOGY AND DISEASE PATHOLOGY. WE PROPOSE TO TEST THE HYPOTHESIS THAT B CELLS IN THE CSF ARE RELATED TO PERIPHERAL B CELLS IN OLD PEOPLE. WE WILL EVALUATE THE PHENOTYPIC NATURE OF CSF VS PERIPHERAL BLOOD B CELLS BY IMMUNOFLUORESCENT STAINING IN OLD AND YOUNG PEOPLE. WE WILL EVALUATE OVERLAP BETWEEN CSF AND PERIPHERAL BLOOD B CELLS BY PCR AMPLIFICATION AND THEN SEQUENCE ANALYSIS OF B CELL-EXPRESSED ANTIBODIES FROM SAMPLES OBTAINED FROM THE SAME INDIVIDUALS AT THE SAME TIME. THIS WORK WILL PROVIDE COMPLETELY NEW INFORMATION CONCERNING THE HYPOTHESIS THAT B CELLS MOVE FROM THE PERIPHERY TO THE CNS IN OLD AGE, AND IN SO DOING CONTRIBUTE TO AGE- ASSOCIATED DEGENERATION AND DISEASE INITIATION AND/OR EXACERBATION. IF TRUE, A NEW PARADIGM WILL FORM FOR FUTURE STUDIES IN BASIC AND CLINICAL NEUROIMMUNOLOGY.

FAIM PROTEOSTASIS IN ALS - SUMMARY THE BROAD, LONG TERM OBJECTIVES OF THIS PROJECT ARE TO ELUCIDATE THE MECHANISMS BY WHICH ABNORMAL PROTEIN AGGREGATION IS HANDLED AT THE CELLULAR LEVEL, AND TO DETERMINE THE RELATIONSHIP BETWEEN ABNORMAL PROTEIN AGGREGATION/DISAGGREGATION AND NEURODEGENERATIVE DISEASE. THE SPECIFIC FOCUS OF THE PRESENT PROPOSAL IS TO STUDY THE INTER-RELATIONSHIPS AMONG A UNIQUE PROTEOSTATIC AGENT (FAIM), ABNORMAL PROTEIN AGGREGATION, AND ALS DISEASE. THE CLINICAL PICTURE OF ALS IS GRIM, WITH MOTOR NEURON LOSS, PROGRESSIVE PARALYSIS, AND DEATH, ALL OCCURRING DURING A BRIEF COURSE OF 2-5 YEARS DURATION. THE ETIOLOGY OF ALS REMAINS UNKNOWN, AND NO INCITING INSULT OR PRECEDING ILLNESS HAS BEEN IDENTIFIED. ELUCIDATION OF ALS PATHOGENESIS IS HAMPERED BY THE SPORADIC NATURE OF MOST CASES, ALTHOUGH A MINORITY (FAMILIAL ALS OR FALS) IS ATTRIBUTABLE TO MUTATION IN ONE OF SEVERAL GENES SUCH AS THE GENE ENCODING SOD1. IMPORTANTLY, REGARDLESS OF SPORADIC OR FAMILIAL ORIGIN, ALL CASES OF ALS ARE CHARACTERIZED BY THE PRESENCE OF ABNORMAL PROTEIN AGGREGATES. BECAUSE SUCH AGGREGATES ARE KNOWN TO BE TOXIC, THIS DYSFUNCTIONAL PROTEIN BEHAVIOR IS THOUGHT TO BE A KEY PATHOGENIC ELEMENT IN ALS. IT HAS BEEN SUGGESTED THAT DISCOVERY OF AN AGENT THAT PREVENTS OR REVERSES PROTEIN AGGREGATION COULD CONSTITUTE A MEANS TO AMELIORATE DISEASE IN ALS. FAIM MAY BE SUCH AN AGENT. ALTHOUGH ORIGINALLY CLONED AS FAS APOPTOSIS INHIBITORY MOLECULE, WE RECENTLY REPORTED THAT FAIM MANIFESTS IMPORTANT PROTEOSTATIC ACTIVITY. IN THE FACE OF VARIOUS FORMS OF STRESS, FAIM INHIBITS ENDOGENOUS PROTEIN AGGREGATION AND, IN KEEPING WITH THIS, FAIM COUNTERACTS LOSS OF VIABILITY IN STRESSED CELLS AND ANIMALS. MOREOVER, FAIM SPECIFICALLY INHIBITS AGGREGATION OF MUTANT SOD1 AND DISAS- SEMBLES ESTABLISHED MUTANT SOD1 AGGREGATES IN CELL-FREE SYSTEMS. WE NOW PROPOSE FURTHER STUDY OF FAIM IN RELATION TO ALS. 1) WE WILL EXAMINE THE CAPACITY OF FAIM TO INFLUENCE AGGREGATION OF ALS-ASSOCIATED MUTANT SOD1 PROTEIN IN HUMAN MOTOR NEURON CELLS DIFFERENTIATED FROM HEALTHY CONTROL IPSC IN WHICH FAIM HAS BEEN DELETED OR OVEREXPRESSED. 2) WE WILL EXAMINE THE CAPACITY OF FAIM TO IMPROVE ALS, BY STUDYING DISEASE ONSET, SEVERITY AND OUTCOME, PLUS TISSUE HISTOLOGIC EXAMINATION, IN MUTANT SOD1 ALS DISEASE MODEL MICE IN WHICH FAIM HAS BEEN DELETED OR OVEREXPRESSED, BOTH GENERALLY AND IN NEURONS. THESE STUDIES WILL LIKELY SHOW THAT FAIM CAN OPPOSE MUTANT PROTEIN AGGREGATION IN HUMAN NEURONS AND CAN IMPROVE ALS DISEASE IN MICE. SUCH RESULTS WOULD PROVIDE PROOF-OF- PRINCIPLE AND SUPPORT FOR THE HYPOTHESIS THAT FAIM CAN BENEFIT OTHER FAMILIAL, AND NON-FAMILIAL, FORMS OF ALS THROUGH ITS PROTEOSTATIC ACTIVITY. FURTHER, SUCH RESULTS WOULD FUEL IMPORTANT CONTINUED STUDY OF FAIM IN CELLULAR STRESS CONDITIONS AND IN OTHER NEURODEGENERATIVE DISEASES. THIS WORK COULD SUGGEST A POTENTIAL THERAPEUTIC ROLE FOR FAIM IN AMELIORATING ALS AND POSSIBLY OTHER NEURODEGENERATIVE DISEASES.

REPROGRAMMING BCR SIGNALING

IGM VS IGG NATURAL ANTIBODIES THAT BIND PATHOGENIC APOLIPOPROTEIN B100

CUX1 AND CELL CYCLE REGULATION IN KIDNEY DEVELOPMENT AND DISEASE

CELLULAR TOOLS FOR STUDYING PKD1 REGULATION IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE - PROJECT SUMMARY AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) IS INCURABLE, AND CELLULAR SYSTEMS FOR MODELING THE GENETICS OF CYSTOGENESIS ARE NEEDED TO UNDERSTAND THE UNDERLYING PATHWAYS AND TO DESIGN PREVENTATIVES. MICE DO NOT FAITHFULLY RECAPITULATE NATURAL ADPKD, PRESENTING A MAJOR LIMITATION TO CYSTOGENESIS RESEARCH. IN HUMANS, CYSTS ARE FORMED WHEN THE PKD1 GENE PRODUCT, POLYCYSTIN-1, IS DISRUPTED. MOST CYSTS ORIGINATE FROM A SOMATIC “SECOND HIT” INACTIVATION OF ONE PKD1 ALLELE, WHICH JOINS THE INHERITED PATHOGENIC ALLELE TO RESULT IN BIALLELIC INACTIVATION. IT HAPPENS HUNDREDS OF TIMES IN HUMAN ADPKD, BUT IN MICE PKD1 HETEROZYGOTES DO NOT FORM CYSTS AND THE GENE ESCAPES MUTATION. WE DISCOVERED WHY, AND WILL USE THAT INFORMATION HERE TO CREATE NOVEL CELLULAR TOOLS FOR ADPKD RESEARCH. WE FIND THAT A DEFINING CHARACTERISTIC OF HUMAN PKD1 IS AN UNUSUAL CAPACITY TO FORM GUANINE-QUADRUPLEX (G4) DNA STRUCTURES. G4 DNA IS FOUND THROUGHOUT THE GENOME WHERE IT HELPS REGULATE GENE EXPRESSION, BUT IT IS UNUSUALLY ABUNDANT IN HUMAN PKD1. G4 DNA IS HIGHLY STABLE IN THE CELL, CONCENTRATED IN THE 5’ REGION OF GENES, AND IS NORMALLY RESOLVED BY G4-SPECIFIC HELICASES TO PREVENT POLYMERASE STALLING AND DNA BREAKS. G4-STABILIZING LIGANDS, REPORTER ASSAYS, AND DIRECT VISUALIZATION IN LIVING CELLS HAS VALIDATED THE CONTRIBUTIONS OF G4 DNA TO CELL PHYSIOLOGY AS WELL AS DOCUMENTED THE PROPENSITY OF THE STRUCTURE TO INCREASE LOCUS-SPECIFIC MUTAGENESIS. HUMAN PKD1 HARBORS ~10-TIMES MORE G4 DNA THAN MOUSE PKD1, AND WE OBSERVED G4 FORMATION IN HUMAN PKD1 BY CHROMATIN IMMUNOPRECIPITATION. INCUBATION OF HUMAN CELLS WITH A G4-STABILIZING LIGAND RESULTED IN DNA BREAKS IN PKD1, AND LOWERED ITS EXPRESSION. G4 DNA DOES NOT MEASURABLY FORM IN MOUSE PKD1 OR CAUSE DNA BREAKS IN THE GENE. SINCE MUTAGENIC INACTIVATION OF HUMAN PKD1 CAUSES CYSTS AND G4 DNA PROVOKES BREAKS IN THE GENE, G4 DNA REGULATES CYSTOGENESIS. BASED ON THAT PREMISE, WE WILL DEVELOP PLURIPOTENT STEM CELLS ALTERED FOR PKD1 G4 CONTENT, THEREBY CREATING A UNIQUE TOOL FOR CYSTOGENESIS RESEARCH. IN AIM 1 WE WILL TRANSFER TWO BLOCKS OF HUMAN PKD1 G4 REPEATS TO MOUSE PKD1 IN INDUCED PLURIPOTENT STEM CELLS, THEREBY HUMANIZING THE MURINE ORTHOLOG IN A CELLULAR SYSTEM CAPABLE OF RENAL CELL DEVELOPMENT. IN AIM 2, WE WILL DELETE TWO G4-RICH REGIONS (INTRONS 21 AND 22) FROM HUMAN PKD1 IN PLURIPOTENT STEM CELLS AND IN HEK293T, PROVIDING TWO NOVEL CELL-BASED REAGENTS FOR STUDYING THE IMPACT OF G4 DNA ON POLYCYSTIN-1 ACTIVITY IN A GENETIC BACKGROUND AMENABLE TO CYSTOGENESIS STUDIES. FOLLOWING THEIR VALIDATION AS G4-MODIFIED PKD1 CELL MODELS, REAGENTS WILL BE MADE FREELY AVAILABLE FOR STUDIES ON ADPKD MECHANISMS AND POTENTIAL THERAPEUTIC INTERVENTIONS.

GUANINE-QUADRUPLEX DNA AND POLYCYSTIC KIDNEY DISEASE

PORT SECURITY GRANT PROGRAM

SUPPORT THE MISSION AND GOALS OF CDC?S GLOBAL HEALTH REGIONALIZATION STRATEGY AND ADVANCE GLOBAL HEALTH SECURITY IN SOUTHEAST ASIA.

HIGHER EDUCATION EMERGENCY RELIEF FUND - INSTITUTIONAL PORTION

SEX SPECIFIC REGULATION OF B1 B CELL SELF-RENEWAL AND NATURAL ANTIBODY PRODUCTION - PROJECT SUMMARY/ABSTRACT LOWER RESPIRATORY TRACT INFECTIONS SUCH AS PNEUMONIA CLAIMS THE LIVES OF APPROXIMATELY 4 MILLION PEOPLE WORLDWIDE EACH YEAR, MAKING THESE INFECTIONS FOURTH ON THE LIST OF GLOBAL CAUSES OF DEATH. STREPTOCOCCUS PNEUMONIAE IS THE MOST COMMON CAUSE OF PNEUMONIA LEADING TO DEATH IN INDIVIDUALS OVER THE AGE OF 65 EIGHT TIMES MORE FREQUENTLY THAN THOSE AGED 5-49, DESPITE THE LONG-STANDING AVAILABILITY OF A VACCINE FOR THIS AGE GROUP (APPROVED IN 1983). IN BOTH MURINE AND HUMAN SYSTEMS, THERE IS A GREATER INCIDENCE OF, AND SUSCEPTIBILITY TO, PNEUMOCOCCAL INFECTION IN MALES; NEVERTHELESS, THE FACTORS CONTRIBUTING TO THIS DIFFERENCE BETWEEN MALES AND FEMALES ARE UNKNOWN. THEREFORE, THE LONG-TERM GOAL OF THIS STUDY IS TO GAIN A GREATER UNDERSTANDING OF THE IMMUNE SYSTEM IN THE CONTEXT OF SEX. SPECIFICALLY, THE GOAL OF THIS PROPOSAL IS TO DETERMINE WHETHER SEX AND/OR ANATOMICAL LOCATION INFLUENCES A SPECIFIC SUBSET OF B CELLS, B1 CELLS, WHICH PROVIDE ESSENTIAL PROTECTION AND THEREFORE SURVIVAL FROM S. PNEUMONIAE INFECTION THROUGH PRODUCTION OF NATURAL ANTIBODIES. ANTIBODIES PROVIDE DEFENSE AGAINST INFECTION BY BINDING THE PATHOGEN AND PREVENTING INFECTION OF HOST CELLS. NATURAL ANTIBODIES ARE PRESENT IN THE ABSENCE OF INFECTION OR INTENTIONAL IMMUNIZATION. B1 CELLS’ UNIQUE ABILITY TO PROVIDE PROTECTION AGAINST S. PNEUMONIAE IS ATTRIBUTED TO THEIR PRODUCTION OF NATURAL ANTIBODIES, WHICH HAVE UNIQUE STRUCTURAL CHARACTERISTICS RESULTING FROM THEIR FETAL DEVELOPMENT. FETAL DERIVED B1 CELLS MAINTAIN THEIR POPULATION THROUGH A SELF-RENEWAL PROCESS, WHICH IS UNLIKE THE B CELL SUBSET, B2 CELLS, GENERATED FROM HEMATOPOIETIC STEM CELLS. THEREFORE, SELF-RENEWAL IS ESSENTIAL FOR THE MAINTENANCE OF NATURAL ANTIBODIES PROTECTIVE AGAINST INFECTION, THOUGH LITTLE IS KNOWN ABOUT HOW SEX INFLUENCES SELF-RENEWAL OF B1 CELLS INTO OLD AGE. WE HAVE DEMONSTRATED NATURAL ANTIBODY FROM AGED MALE MICE DOES NOT PROVIDE PROTECTION AGAINST S. PNEUMONIAE INFECTION WHEREAS, NATURAL ANTIBODY FROM AGED FEMALES MAINTAINS ITS PROTECTIVE CAPACITY. WE HYPOTHESIZE THAT MAINTENANCE OF B1 CELLS THROUGH SELF-RENEWAL IS INFLUENCED BY SEX DURING AGING. WE POSTULATE THAT FEMALE B1 CELLS MAINTAIN MORE PRODUCTIVE B1 SELF-RENEWAL ALLOWING FOR THE DIFFERENCES SEEN IN SUSCEPTIBILITY TO INFECTION WITH SEX AND AGE. TO TEST THIS HYPOTHESIS, WE WILL PERFORM THE FOLLOWING AIMS: 1) ELUCIDATE THE SEX-SPECIFIC DEVELOPMENTAL DIFFERENCES REGULATING B1 CELLS BY EXAMINING CELL CYCLE MAINTENANCE THROUGH A UNIQUE TRANSGENIC REPORTER LINE COMBINED WITH EXAMINATION OF SELF-RENEWAL TO DETERMINE THE FUNCTIONAL CONSEQUENCE OF SEX, AGE, AND CELL CYCLE ACTIVITY ON THE PRODUCTION OF PROTECTIVE ANTIBODY AND 2) DETERMINE HOW MAINTENANCE OF SELF-RENEWAL IN HUMANS MAY MIRROR THE MURINE SYSTEM AND INFLUENCE PRODUCTION OF NATURAL ANTIBODY. THIS PROJECT WILL DETERMINE HOW SEX INFLUENCES THE MAINTENANCE OF B1 CELL SELF-RENEWAL AND THE SUBSEQUENT IMPACT ON THE PRODUCTION OF NATURAL ANTIBODIES DURING AGING. THIS FURTHER UNDERSTANDING OF THE IMMUNE SYSTEM IN CONTEXT TO SEX WILL LIKELY SUGGEST NEW PREVENTION AND/OR TREATMENT STRATEGIES OF S. PNEUMONIAE INFECTION IN BOTH MALE AND FEMALE AGING POPULATIONS.

FY 2020 HEALTH CENTER PROGRAM LOOK-ALIKES: EXPANDING CAPACITY FOR CORONAVIRUS TESTING

ASSISTANCE TO FIREFIGHTERS GRANT

A MEMORY CD4 T-CELL BIOMARKER PREDICTS T1D PROGRESSION AND TREATMENT RESPONSE

EMERGENCY FINANCIAL AID GRANTS TO STUDENTS UNDER THE CORONAVIRUS AID, RELIEF, AND ECONOMICSECURITY (CARES)ACT.

FY 2023 EXPANDING COVID-19 VACCINATION

THE SEVERE SHORTAGE OF FORENSIC PATHOLOGISTS HAS BECOME A CRISIS IN COMMUNITIES THROUGHOUT OUR COUNTRY, WHICH THE OPIOID EPIDEMIC AND COVID-19 HAVE ONLY EXACERBATED. AS A RESULT, WE DEVELOPED A HIGH-QUALITY FORENSIC PATHOLOGY FELLOWSHIP AT THE WESTERN MICHIGAN UNIVERSITY HOMER STRYKER M.D. SCHOOL OF MEDICINE (WMED). THE TEAM, COMPRISED OF SEVEN FORENSIC PATHOLOGISTS, TWO FORENSIC ANTHROPOLOGISTS, A FORENSIC TOXICOLOGIST, AND MULTIPLE DEATH INVESTIGATORS, LEADS THE FORENSIC PATHOLOGY TRAINING PROGRAM. THE WMED PROVIDES THEIR FELLOWS WITH BEST-PRACTICE TRAINING AND OPPORTUNITIES TO BECOME LEADERS IN FORENSIC PATHOLOGY. SINCE THE START OF THE PROGRAM IN 2020, THEY GRADUATED ONE FORENSIC PATHOLOGIST WHO HAS NOW JOINED OUR FACULTY AND A SECOND WILL GRADUATE AND BEGIN PRACTICING FORENSIC PATHOLOGY IN FLORIDA IN JULY OF 2022. FORENSIC PATHOLOGY FELLOWSHIP PROGRAMS ACCREDITED BY THE ACCREDITATION COUNCIL ON GRADUATE MEDICAL EDUCATION AND OPERATING IN MEDICAL EXAMINER’S OFFICES ACCREDITED BY THE NATIONAL ASSOCIATION OF MEDICAL EXAMINERS REQUIRE FUNDING TO TRAIN FUTURE FORENSIC PATHOLOGISTS AND WMED IS NO EXCEPTION. WHILE MOST MEDICAL SPECIALTIES RECEIVE FUNDING FOR RESIDENCIES AND FELLOWSHIPS FROM MEDICARE AND OCCASIONALLY MEDICAID, FORENSIC PATHOLOGY OFTEN REQUIRES FUNDING FROM OTHER SOURCES. THE SHORTAGE OF FORENSIC PATHOLOGISTS IS EXACERBATED WHEN FELLOWSHIP POSITIONS LACK FUNDING SOURCES. FUNDING FOR THE FELLOWSHIP ALLOWS THE WMED TO MAINTAIN THE OPERATION OF THE PROGRAM. ADVANCING EQUITY IS A COMMITMENT THAT REQUIRES SUSTAINED EFFORTS AND LEADERSHIP. WMED'S ABILITY TO ADDRESS POTENTIAL INEQUITIES AND BARRIERS TO EQUAL OPPORTUNITY IS MORE ROBUST THAN MOST INSTITUTIONS. THE STUDENTS WMED WILL BE RECRUITING WILL SOON BENEFIT FROM THE MEDICAL SCHOOL’S FOCUS ON RECRUITING STUDENTS FROM DISENFRANCHISED GROUPS WHO OFTEN FACE BARRIERS TO HIGHER EDUCATION, AN INITIATIVE BACKED BY A $300 MILLION GIFT TO PROMOTE DIVERSITY, EQUITY, AND INCLUSION. THE GIFT IS EARMARKED FOR SCHOLARSHIPS TO REDUCE FINANCIAL BARRIERS FOR FUTURE DOCTORS AND ALLOW THE MEDICAL SCHOOL TO RECRUIT MORE DIVERSE STUDENT COHORTS. THE WMED'S COMMUNITIES ARE UNDERSERVED, BUT MORE THAN SIMPLY TRAINING MORE INDIVIDUALS, THE INSTITUTION PRIORITIZES TRAINING INDIVIDUALS COMMITTED TO SERVING UNDERSERVED POPULATIONS. BEING PHYSICALLY BASED IN A MEDICAL SCHOOL ALLOWS THE WMED ACCESS TO NEW MEDICAL STUDENTS EACH YEAR; THE FELLOW ALONG WITH THE PRACTICING FORENSIC PATHOLOGISTS ARE PROVIDED WITH MULTIPLE OPPORTUNITIES TO PROMOTE FORENSIC PATHOLOGY AMONG THE MEDICAL STUDENT BODY. IN CONCLUSION, IN ADDITION TO TRAINING ADDITIONAL FORENSIC PATHOLOGISTS, ACCESS TO THE STUDENTS AND THEIR EXPOSURE TO FORENSIC PATHOLOGY WILL RESULT IN A HIGHER-THAN-AVERAGE NUMBER OF STUDENTS PURSUING FORENSIC PATHOLOGY AS THEIR CAREER CHOICE.

HPAI

B1A CELL FUNCTION IN SICKLE CELL DISEASE

THE DEPARTMENT OF PATHOLOGY DEVELOPED A HIGH-QUALITY FORENSIC PATHOLOGY FELLOWSHIP AT THE WESTERN MICHIGAN UNIVERSITY HOMER STRYKER M.D. SCHOOL OF MEDICINE (WMED). AT WMED, THE MEDICAL EXAMINERS OFFICE SERVES THIRTEEN COUNTIES IN MICHIGAN, WITH ADDITIONAL POSTMORTEM EXAMINATION COVERAGE FOR COUNTIES WITHOUT ACCESS TO A FORENSIC PATHOLOGIST. THE LEADERSHIP OF THIS PROGRAM IS COMPRISED OF SIX (SEVEN WHEN FULLY STAFFED) FORENSIC PATHOLOGISTS (ONE OF WHICH IS ALSO A NEUROPATHOLOGIST), TWO FORENSIC ANTHROPOLOGISTS, A FORENSIC TOXICOLOGIST, AND SEVERAL MEDICOLEGAL DEATH INVESTIGATORS. FELLOWS ARE PROVIDED WITH BEST-PRACTICE TRAINING AND OPPORTUNITIES TO BECOME LEADERS IN FORENSIC PATHOLOGY. IN ADDITION TO TRAINING ADDITIONAL FORENSIC PATHOLOGISTS, ACCESS TO STUDENTS AND THEIR EXPOSURE TO FORENSIC PATHOLOGY WILL RESULT IN A HIGHER-THAN-AVERAGE NUMBER OF STUDENTS PURSUING FORENSIC PATHOLOGY AS THEIR CAREER CHOICE.

UNDERSTANDING THE LINK BETWEEN FAIM EXPRESSION AND ALZHEIMER?S DISEASE AND RELATED DEMENTIAS - DEMENTIA IS A PROGRESSIVE, INCURABLE, AND UNIFORMLY FATAL NEURODEGENERATIVE DISORDER. ALZHEIMER’S DISEASE (AD) IS THE PRIMARY CAUSE OF PROGRESSIVE DEMENTIA, FOLLOWED BY LEWY BODY DEMENTIA AND FRONTOTEMPORAL DEMENTIA (FTD). THE PREVALENCE OF AD AND RELATED DEMENTIAS (ADRD) INCREASES WITH AGE. WITH INCREASING LONGEVITY WORLDWIDE, THE SOCIETAL IMPACT OF ADRD WILL BECOME MORE SEVERE. A COMMON, PATHOLOGICAL HALLMARK OF THESE DEMENTIAS IS THE ACCUMULATION OF ABNORMAL A-SYNUCLEIN (A-SYN), AMYLOID-SS (ASS) AND TAU SPECIES IN AND AROUND AFFECTED TISSUES, LEADING TO NEURONAL CELL DEATH. ALTHOUGH TREATMENTS ARE AVAILABLE TO RELIEVE SOME ADRD SYMPTOMS, CURRENT THERAPEUTIC INTERVENTIONS FOR ADRD ARE INSUFFICIENT AS THEY FAIL TO MODIFY DISEASE PROGRESSION BY AMELIORATING THE UNDERLYING PATHOLOGY. IT HAS BEEN SUGGESTED THAT DISCOVERY OF A MOLECULE THAT COULD PREVENT OR REVERSE NEUROTOXIC FORMS OF A-SYN, ASS AND TAU SPECIES SUCH AS OLIGOMERS AND FIBRILS COULD SLOW OR REVERSE ADRD DISEASE. WE RECENTLY IDENTIFIED FAS APOPTOSIS INHIBITORY MOLECULE (FAIM), WHICH CAN PREVENT AND REVERSE PATHOGENIC A-SYN, ASS AND TAU SPECIES IN VITRO, SUGGESTING THAT FAIM MIGHT FULFIL A KEY ROLE IN ANTAGONIZING THESE PATHOGENIC SPECIES IN VIVO. FURTHERMORE, IT HAS BEEN REPORTED THAT FAIM EXPRESSION IS REDUCED IN THE HIPPOCAMPAL SAMPLES FROM AD PATIENTS, ESPECIALLY IN THE LATE BRAAK STAGES, FURTHER SUGGESTING A ROLE IN DISEASE. IN SPITE OF COMPELLING DATA ON FAIM ACTIVITY IN VITRO AND OF LOW FAIM EXPRESSION IN AD BRAIN, WHETHER AND TO WHAT EXTENT FAIM IS INVOLVED IN THE PREVENTION/CLEARANCE OF THE NEUROTOXIC PROTEINS IN NEURONS, AND WHAT REGULATES FAIM EXPRESSION IN NEURONS STILL REMAINS UNEXPLORED. THE LONG-TERM GOAL OF THIS STUDY IS TO GAIN A GREATER COMPREHENSION OF BASIC MOLECULAR MECHAISMS OF FAIM FUNCTION/EXPRESSION IN ADRD, WHICH MAY ENABLE DEVELOPMENT OF NEW PREVENTIVE OR DISEASE-MODIFYING STRATEGIES THAT ELIMINATE NEUROTOXIC A-SYN, ASS AND TAU SPECIES IN ADRD PATIENTS TO SLOW OR REVERSE ADRD SYMPTOMS. SPECIFICALLY, THE IMMEDIATE GOALS OF THIS PROPOSAL ARE TO IDENTIFY FACTORS REGULATING FAIM EXPRESSION IN CORTICAL NEURONS DERIVED FROM HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSCS). WE WILL FURTHER DETERMINE WHETHER AND TO WHAT EXTENT FAIM-DEFICIENCY OR FAIM-OVEREXPRESSION AFFECTS THE LEVELS OF PATHOGENIC TAU SPECIES USING FAIM-DEFICIENT OR FAIM-OVEREXPRESSING CORTICAL NEURONS. THE PROPOSED STUDY WILL DETERMINE FOR THE FIRST TIME WHETHER FAIM EXPRESSION LEVELS ARE ASSOCIATED WITH ADRD PATHOGENESIS THROUGH MODIFYING THE FORMATION OF PATHOGENIC PROTEIN SPECIES IN ADDITION TO THE MOLECULAR MECHANISM OF HUMAN FAIM GENE REGULATION IN NEURONS. THIS WORK HAS THE POTENTIAL TO ADD A NEW LAYER OF UNDERSTANDING IN THE PATHOPHYSIOLOGY OF ADRD ONSET AND PROGRESSION, WHICH MIGHT BE ASSOCIATED WITH FAIM EXPRESSION AND ITS REGULATORS. THIS WILL PROVIDE NEW INSIGHTS INTO THE INTERRELATIONSHIP AMONG FAIM EXPRESSION AND ITS REGULATORS, PROTEIN OLIGOMERIZATION/FIBRILLIZATION, AND THE ADRD PATHOGENESIS.

THE DECISION TO PURSUE ACCREDITATION FOR A MEDICOLEGAL DEATH INVESTIGATION SYSTEM BY THE NATIONAL ASSOCIATION OF MEDICAL EXAMINERS (NAME) STEMS FROM A DESIRE BY THE LEADERSHIP TO DEMONSTRATE CONFIDENCE THAT THE MEDICAL EXAMINER'S OFFICE IS COMMITTED TO PROVIDING A SYSTEM WORTHY OF THE PUBLIC’S TRUST. PURSUING NAME ACCREDITATION REQUIRES DEDICATED STAFF AND FACULTY WITH THE TIME AND RESOURCES TO MEET THESE STANDARDS. LIKE MOST OTHER MEDICAL EXAMINER’S OFFICES (MEOS) ACROSS THE COUNTRY, THE MEO LOCATED WITHIN THE DEPARTMENT OF PATHOLOGY AT THE WESTERN MICHIGAN UNIVERSITY HOMER STRYKER M.D. SCHOOL OF MEDICINE (WMED) IS CHALLENGED WITH STAFFING SHORTAGES AND SIGNIFICANTLY INCREASED NUMBERS OF DEATHS RELATED TO THE COVID-19 PANDEMIC. SERVING 13 COUNTIES AS THE MEDICAL EXAMINER IN MICHIGAN AND PROVIDING SEVERAL OTHER COUNTIES WITH CONSULTANT FORENSIC PATHOLOGY SERVICES, THIS SURGE OF DEATHS HAS PLACED A GREATER BURDEN ON AUTOPSY AND ADMINISTRATIVE STAFF THAN EVER BEFORE. IN 2021, OVER 1,500 POSTMORTEM EXAMINATIONS WERE PERFORMED. THIS PROJECT PROPOSES THE HIRING OF A PART-TIME PROJECT COORDINATOR (PC) DEDICATED TO ENSURING THAT THE MEO IS MEETING AND/OR SURPASSING STANDARDS SET FORTH BY NAME. THE MEO AT WMED HAS BEEN NAME-ACCREDITED SINCE 2016. THIS STATUS ASSISTS IN HIRING PROCESSES, ESPECIALLY THAT OF HIGHLY QUALIFIED FORENSIC PATHOLOGISTS, WHICH ARE SEVERELY LACKING ACROSS THE U.S. THIS ACCREDITATION ALSO PROVIDES ASSURANCE TO THE COMMUNITIES SERVED BY THE MEO REGARDING THE PERFORMANCE OF HIGH QUALITY EXAMINATIONS AND THE OFFICE’S COMMITMENT TO SUPPORTING PUBLIC HEALTH INITIATIVES. THE PC WILL WORK ALONGSIDE THE QUALITY AND RESEARCH MANAGER TO PERFORM QUARTERLY INSPECTIONS THAT WILL INFORM THE TEAM OF FORENSIC PATHOLOGISTS, AUTOPSY STAFF, LABORATORY DIRECTORS AND TECHNICIANS, SCENE INVESTIGATORS AND ADMINISTRATIVE STAFF. THE PC WILL ASSIST WITH THE REVIEW AND REVISION OF ALL POLICIES AND PROCEDURES REQUIRED BY NAME AND WILL AID IN THE GATHERING OF COMPLETE DATA VIA THE WEB-BASED CASE MANAGEMENT SYSTEM FOR ANNUAL STATISTICAL COMPILATION, ANALYSIS AND DISSEMINATION. THE PC WILL BE RESPONSIBLE FOR THE INPUT OF ALL NAME ACCREDITATION-RELATED MATERIALS TO THE WEB-BASED INSPECTION AND ACCREDITATION PROGRAM ANNUALLY AND WILL PLAY A LARGE ROLE IN THE NEXT SCHEDULED SITE VISIT CURRENTLY SET FOR JANUARY OF 2024. THIS INDIVIDUAL’S FOCUS ON NAME REQUIREMENTS WILL PLAY A VITAL ROLE IN CONTINUED ACCREDITATION OF THE MEO AT WMED.

STRENGTHENING THE MEDICAL EXAMINER - CORONER SYSTEM FELLOWSHIP PROGRAM IN THE MIDWEST

PORT SECURITY GRANT PROGRAM

NEGOTIATING CREW AUTONOMY DURING SPACE OPERATIONS

IMPROVE EXISTING AIRPORT C

EFFICACY OF LIGHT-ACTIVATED ANTI-MICROBIAL FABRICS AGAINST HUMAN PATHOGENS

DURABLE VISIBLE LIGHT-ACTIVATED ANTIVIRAL COATINGS FOR FABRICS USED FOR PERSONAL

PURPOSE: TO SUPPORT PERSONNEL AND FACILITIES EXPENSES IN RESPONSE TO AND RECOVERY FROM THE COVID-19 PANDEMIC.

ASSISTANCE TO FIREFIGHTERS GRANT

THE MEDICAL EXAMINERS OFFICE AT WESTERN MICHIGAN UNIVERSITY HOMER STRYKER M.D. SCHOOL OF MEDICINE (WMED) SERVES THIRTEEN COUNTIES IN MICHIGAN AS THE MEDICAL EXAMINER AND PROVIDES SEVERAL OTHER COUNTIES WITH POSTMORTEM EXAMINATION SERVICES. THE MEDICAL EXAMINERS OFFICE AT WMED HAS BEEN ACCREDITED THROUGH NAME SINCE 2016. NAME ACCREDITATION STATUS ASSISTS IN HIRING PROCESSES, ESPECIALLY THAT OF HIGHLY QUALIFIED FORENSIC PATHOLOGISTS, AND PROVIDES ASSURANCE TO COMMUNITIES SERVED REGARDING THE OFFICES COMMITMENT TO SUPPORTING PUBLIC HEALTH INITIATIVES AND UPHOLDING THE PUBLICS TRUST. MUCH LIKE OTHERS ACROSS THE COUNTRY, THE MEDICAL EXAMINERS OFFICE AT WMED HAS BEEN CHALLENGED WITH SUBSTANTIAL INCREASES IN REPORTED DEATHS AND SUBSEQUENT INCREASES IN POSTMORTEM EXAMINATIONS. IN 2022, OVER 1600 POSTMORTEM EXAMINATIONS WERE PERFORMED. THIS, IN ASSOCIATION WITH STAFFING SHORTAGES, MAKES MAINTAINING NAME ACCREDITATION A DIFFICULT TASK FOR ANY OFFICE. THIS PROJECT PROPOSES A CONTINUATION OF A PART-TIME PROJECT COORDINATOR, CURRENTLY TITLED ACCREDITATION SPECIALIST, DEDICATED TO ENSURING THAT THE MEDICAL EXAMINERS OFFICE IS MEETING AND/OR SURPASSING STANDARDS SET FORTH BY NAME. THE ACCREDITATION SPECIALIST WILL CONTINUE TO WORK ALONGSIDE THE SENIOR MANAGER FOR RESEARCH AND AUTOPSY OPERATIONS TO PERFORM QUARTERLY INSPECTIONS THAT INFORM THE EXPANSIVE TEAM OF FORENSIC PATHOLOGISTS, FELLOW(S), AUTOPSY STAFF, LABORATORY DIRECTORS AND TECHNICIANS, MEDICOLEGAL DEATH INVESTIGATORS, AND ADMINISTRATIVE STAFF. THE ACCREDITATION SPECIALIST WILL COORDINATE AND ASSIST IN THE REVIEW AND REVISION OF ALL POLICIES AND PROCEDURES REQUIRED BY NAME AND WILL PLAY A VITAL ROLE IN DATA GATHERING FOR ANNUAL STATISTICAL COMPILATION, ANALYSIS AND DISSEMINATION VIA THE WEB-BASED CASE MANAGEMENT SYSTEM USED TO TRACK AND FILE ALL REPORTED DEATHS. ALSO, THE ACCREDITATION SPECIALIST WILL CONTINUE TO BE RESPONSIBLE FOR THE ANNUAL INPUT OF ALL REQUIRED DOCUMENTATION TO THE WEB-BASED INSPECTION AND ACCREDITATION PROGRAM EMPLOYED TO ASSESS CONTINUED NAME COMPLIANCE. THIS DEVOTED INDIVIDUAL TO NAME COMPLIANCE WILL PLAY A VITAL ROLE IN CONTINUED ACCREDITATION OF THE MEDICAL EXAMINERS OFFICE AT WMED.

REAP RENEWABLE ENERGY SYSTEM (RES) GRANT UNRESTRICTED AMOUNT - IRA 24/31

PROMOTE AWARENESS OF

TO INCREASE PARTICIPATION IN NRCS FINANCIAL PROGRAMS, SPECIFICALLY EQIP, BY PROVIDING IN-PERSON OUTREACH MEETINGS AND DEMONSTRATIONS THAT PROMOTE THE ADOPTION OF USDA-NRCS CLIMATE SMART PRACTICES.

EMSC TARGETED ISSUE GRANTS

REAP RENEWABLE ENERGY SYSTEM (RES) GRANT UNRESTRICTED AMOUNT

ASSISTANCE TO FIREFIGHTERS GRANT

PURPOSE: TO SUPPORT STAFF SALARIES FOR YEAR-ROUND CURATED FILM SCREENINGS PUBLIC ENGAGEMENT ACTIVITIES AND EDUCATIONAL PROGRAMS.

PURPOSE: TO SUPPORT YEAR-ROUND CURATED FILM SCREENINGS, PUBLIC ENGAGEMENT ACTIVITIES, AND EDUCATIONAL PROGRAMS.

ASSISTANCE TO FIREFIGHTERS GRANT

FY 2023 BRIDGE ACCESS PROGRAM

PURPOSE: TO SUPPORT CURATED FILM SCREENINGS, PUBLIC ENGAGEMENT ACTIVITIES, AND EDUCATIONAL PROGRAMS.

PURPOSE: TO SUPPORT YEAR-ROUND CURATED SCREENINGS PUBLIC ENGAGEMENT ACTIVITIES AND EDUCATIONAL PROGRAMS.

ASSISTANCE TO FIREFIGHTERS GRANT

ASSISTANCE TO FIREFIGHTERS GRANT

SEC. 9007 REAP-ENERGY EFFICIENCY IMPROVEMENTS GRANTS (MAN)

PURPOSE: TO SUPPORT YEAR-ROUND CURATED SCREENINGS PUBLIC ENGAGEMENT ACTIVITIES AND EDUCATIONAL PROGRAMS.

SMALL, RURAL SCHOOL ACHIEVEMENT PROGRAM

CONSERVATION TECHNICAL ASSISTANCE - GE

ASSISTANCE TO FIREFIGHTERS GRANT

"THE MOUNT VERNON HOTEL MUSEUM AND GARDEN WILL IMPLEMENT A CULTURAL ARTS PILOT PROGRAM FEATURING MUSEUM VISITS AND CLASSROOM WORKSHOPS FOR CULTURALLY UNDERSERVED STUDENTS FROM GRADES 4-6 IN AN ECONOMICALLY DEPRESSED SECTION OF THE BRONX, NEW YORK. THE PROJECT WILL ADDRESS THE LACK OF ARTS TEACHERS IN LOCAL SCHOOLS, THE DEVELOPMENT OF VISUAL LITERACY, CRITICAL THINKING SKILLS, AND HISTORICAL EMPATHY THROUGH THE ARTS. THE FOCAL POINT OF THE PROJECT WILL BE AN INTENSIVE SCHOOL-MUSEUM PROGRAM SERVING AN ESTIMATED 360 CHILDREN. MUSEUM STAFF, VOLUNTEERS, AND CLASSROOM TEACHERS WILL PARTICIPATE IN TRAINING PRIOR TO BEGINNING THE PROGRAM. A CULMINATING FAMILY DAY FOR PARENTS, CAREGIVERS, AND THE STUDENTS WILL PROVIDE AN OPPORTUNITY FOR STUDENTS TO DISPLAY THEIR ART WORK PRODUCED DURING THE PROJECT. AN EVALUATION CONSULTANT WILL USE SURVEYS, INTERVIEWS WITH TEACHERS, AND OTHER TOOLS TO MEASURE THE PROJECT'S SUCCESS IN ACHIEVING OUTCOMES FOR STUDENTS."

SMALL, RURAL SCHOOL ACHIEVEMENT PROGRAM

SMALL, RURAL SCHOOL ACHIEVEMENT PROGRAM

THE MOUNT VERNON HOTEL MUSEUM AND GARDEN WILL IMPLEMENT A COMPREHENSIVE PROGRAM OF FREE COMMUNITY WORKSHOPS AND SPANISH-LANGUAGE MUSEUM TOURS. THE PROJECT IS DESIGNED TO EXPAND THE MUSEUM?S REACH AND INCREASE ENGAGEMENT WITH ITS EAST HARLEM NEIGHBORHOOD AND NEW YORK CITY?S LATINO POPULATION. THE MUSEUM WILL HOLD 10 WORKSHOPS AT COMMUNITY PARTNERS? LOCATIONS, AT WHICH STAFF WILL OFFER AN INTRODUCTION TO THE MUSEUM. PARTICIPANTS WILL ATTEND A SPANISH-LANGUAGE TOUR OF THE MUSEUM DURING ONE SATURDAY EACH MONTH. EACH TOUR WILL HAVE A THEME THAT WILL HIGHLIGHT LATIN AMERICAN AND CARIBBEAN INFLUENCES ON 19TH CENTURY NEW YORK CITY.

TO SUPPORT THE 15TH FILM FESTIVAL VIS VIENNA INDEPENDENT SHORTS, AN INTERNATIONAL FESTIVAL FOR SHORT FILM, ANIMATION AND MUSIC VIDEO.

SMALL, RURAL SCHOOL ACHIEVEMENT PROGRAM

SMITH'S CASTLE UV WINDOW FILM PROJECT

SEC. 9007 REAP-ENERGY EFFICIENCY IMPROVEMENTS GRANTS (MAN)

CONFERENCES MARKETS AND OUTREACH OH MY A COLLABORATIVE EFFORT TO ENGAGE AND EMPOWER ALABAMA CITIZENS THROUGH GARDENING

REAP IRA RES GRANT UNRESTRICTED (FY 25)

INVESTIGATIONS ON THE CELLULAR AND MORPHOLOGIC CHARACTERISTICS OF CRANIAL VAULT FRACTURE: RESEARCH AND DEVELOPMENT OF A TIME SINCE FRACTURE PROTOCOL AND DATABASE

EMSC TARGETED ISSUE GRANTS

SEC. 9007 REAP-RENEW ENERGY SYS GRANTS (MAN)