Loma Linda Veterans Association For Research And Education

MOLECULAR MECHANISM OF SOFT TISSUE REGENERATION AND BONE FORMATION IN MICE: IMPLICATIONS IN FRACTURE REPAIR AND WOUND HEALING IN HUMANS

TRANSGENIC APPROACHES TO EVALUATE IGF-I ROLE IN PEAK BMD

OTOACOUSTIC EMISSION COCHLEOGRAPHY

PREVENTING OTOTOXIC SYNERGY OF PRIOR NOISE TRAUMA DURING AMINOGLYCOSIDE THERAPY

ENDOSTEAL BONE VOLUME REGULATION AND OSTEOPOROSIS

ROLE AND MECHANISM OF CLAUDIN-11 ACTION AND SIGNALING IN BONE

HEARING LOSS AND THE PERCEPTION OF COMPLEX SOUND

A COMPARATIVE APPROACH TO HUMAN AUDITORY SYNAPTOPATHY

MOLECULAR MECHANISMS OF LRRK1 REGULATION OF BONE HOMEOSTASIS - PROJECT SUMMARY/ABSTRACT LEUCINE RICH REPEAT KINASE 1 (LRRK1), A NOVEL SERINE/THREONINE KINASE, IS EXPRESSED IN BONES, BRAIN AND OTHER TISSUES. WE RECENTLY DEMONSTRATED THAT LRRK1 GENE KNOCKOUT (KO) MICE AS WELL AS A PATIENT WITH A LRRK1 GENE MUTATION ARE SEVERELY OSTEOPETROTIC DUE TO OSTEOCLAST DYSFUNCTION AND REDUCED BONE RESORPTION IN LONG AND VERTEBRA BONES. MORE IMPORTANTLY, LRRK1 KO MICE HAD LIFELONG BONE ACCUMULATION AND RESPONDED NORMALLY TO THE ANABOLIC ACTIONS OF TERIPARATIDE TREATMENT BUT WERE RESISTANT TO OVARIECTOMY (OVX)-INDUCED BONE BOSS. THESE OBSERVATIONS MAKE LRRK1 AN IDEAL TARGET OF A NOVEL ANTI-RESORPTION DRUGS FOR TREATMENT OF OSTEOPOROSIS. IN THIS GRANT, OUR FOCUS IS TO PERFORM IN VIVO AND IN VITRO STUDIES TO STUDY THE ROLE OF LRRK1-MEDIATED PHOSPHORYLATION OF OSTEOPETROSIS SPECIFIC TRANSMEMBRANE PROTEIN 1 (OSTM1) IN THE REGULATION OF CHLORIDE CHANNEL 7 (CLC7) COMPLEX STABILIZATION, LYSOSOMAL PERIPHERAL MOVEMENT, LYSOSOMAL ACID SECRETION AND OC FUNCTION. TO THIS END, WE HYPOTHESIZE THAT LRRK1 PHOSPHORYLATION OF OSTM1 AT RESIDUES OF THREONINE 328 AND SERINE 329 REGULATES OC FUNCTION AND BONE RESORPTION BY STABILIZATION OF OSTM1/CLC7 COMPLEX AND PROMOTION OF LYSOSOMAL PERIPHERAL MOVEMENT AND LYSOSOMAL ACID SECRETION INTO LACUNA IN VIVO. FOUR-YEAR STUDIES PROPOSED IN THIS GRANT WILL DELIVER THE ROLE OF LRRK1 PHOSPHORYLATION OF THREONINE AND SERINE RESIDUES OF OSTM1 IN REGULATION OF BONE RESORPTION IN VITRO AND IN VIVO. THE RESULTS OF THIS APPLICATION WILL HELP OUR UNDERSTANDING OF MOLECULAR MECHANISMS OF LRRK1 AND OSTM1 ACTIONS IN OSTEOCLAST AND DEVELOP POTENTIAL INHIBITORS OF LRRK1 FOR TREATMENT OF OSTEOPOROSIS IN FUTURE.

EXPLORING OTOACOUSTIC EMISSIONS WITH INTRACOCHLEAR PRESSURE AND MOTION MEASUREMEN

A NOVEL EPHA4-BASED SMALL MOLECULE-BASED THERAPEUTIC STRATEGY FOR PREVENTION AND TREATMENT OF POST TRAUMATIC OSTEOARTHRITIS

ROLE OF ORGAN OF CORTI OUTER HAIR CELL/VIBRATION HOT SPOTS IN DISTORTION PRODUCT OTOACOUSTIC EMISSION GENERATION - PROJECT SUMMARY/ABSTRACT EARLIER RESEARCH IN OUR LABORATORY USING INTERFERENCE TONES (ITS) AND VECTOR-DIFFERENCE ANALYSES BETWEEN CONTROL AND VARIOUS EXPERIMENTAL CONDITIONS ESTABLISHED THAT LARGE DISTORTION PRODUCT OTOACOUSTIC EMISSIONS (DPOAES) COMPONENTS EVIDENCED BY STRONG ENHANCEMENT AND/OR SUPPRESSION, CAN ARISE FROM REGIONS LOCATED UP TO SEVERAL OCTAVES BASAL TO THE F2 PRIMARY-TONE. THE PROPOSED EXPERIMENTS IN GERBILS ARE FOCUSED ON IDENTIFYING A PHYSICAL MECHANISM IN COCHLEAR MICROMECHANICS THAT EXPLAINS THE EXISTENCE OF SUCH BASAL DPOAE COMPONENTS. SPECIFICALLY, THE STUDIES DESCRIBED BELOW ARE AIMED AT SHOWING THAT BASAL COMPONENTS ARE PRODUCED BY RECENTLY DESCRIBED NONLINEAR VIBRATION HOTSPOTS (VHSS) THAT LOCALIZE TO THE OUTER HAIR CELL (OHC) REGION. THESE OHC/VHSS, UNLIKE THE BM, ARE NONLINEAR OVER MANY OCTAVES BELOW THE MEASUREMENT BF, AND ARE CAPABLE OF GENERATING PHYSICAL MOTIONS SIGNIFICANTLY LARGER THAN THEIR COUNTERPART BM VIBRATIONS. METHODS WILL UTILIZE NONINVASIVE OPTICAL COHERENCE TOMOGRAPHY (OCT) THAT IS CAPABLE OF MEASURING VIBRATIONS OF VARIOUS SUBCOMPONENTS OF THE ORGAN OF CORTI, ALONG WITH THE SIMULTANEOUS RECORDINGS OF INTRACOCHLEAR DISTORTION PRODUCTS (IDPS) AND EAR-CANAL DPOAES. IN THIS MANNER, OHC/VHSS WILL BE LINKED TO THE NONAMPLIFYING WIDELY DISTRIBUTED NONLINEARITY HYPOTHESIZED TO BE THE SOURCE OF BASALLY GENERATED DPOAE COMPONENTS, THUS, PROVIDING A DIRECT PHYSICAL MECHANISM FOR THEIR GENERATION. BRIEFLY, AIM 1 UTILIZES OCT TO CHARACTERIZE IDPS FROM THE BM AND OHC/VHS REGIONS SIMULTANEOUSLY AS A FUNCTION OF PRIMARY-TONE LEVELS AND F2/F1 RATIOS AS THE PRIMARY-TONES ARE STEPPED APICALLY PAST THE BEST FREQUENCY (BF) OF THE OCT-MEASUREMENT LOCATION. FOURIER TRANSFORMS OF THE VIBRATIONS FROM THE BM AND THE OHC/VHSS WILL BE PERFORMED TO EXTRACT IDPS FROM THESE SUBCOMPONENTS. NEXT, ITS AND BRIEF NOISE OVEREXPOSURES WILL BE USED TO LINEARIZE THE NONAMPLIFYING NONLINEARITY OF THE OHC/VHSS WHILE SIMULTANEOUSLY MEASURING EAR-CANAL DPOAES. VECTOR SUBTRACTION WILL BE USED TO ISOLATE COMPONENTS THAT ARE HYPOTHESIZED TO BE RESPONSIBLE FOR GENERATING BASAL DPOAE COMPONENTS. IN AIM 2, FUROSEMIDE ADMINISTRATION WILL BE EMPLOYED TO TEMPORARILY ELIMINATE OHC/VHSS AND BM IDPS, THEREBY INTERFERING WITH BOTH THE BROADLY DISTRIBUTED OHC/VHS NONLINEARITY AND THE BM AMPLIFYING PEAK NONLINEARITY, WHICH HAVE BEEN SHOWN TO EXHIBIT DIFFERENT RECOVERY-TIME COURSES. IN THIS MANNER, CONTRIBUTIONS FROM THE BM PEAK AND BROADBAND NONLINEARITIES CAN BE SEPARATED. AGAIN, BASAL IDP AND DPOAE COMPONENTS WILL BE EXTRACTED BY VECTOR SUBTRACTION OF THESE MEASURES BEFORE AND AFTER THE ABOVE INTERVENTIONS. THE EXPECTED OUTCOMES OF THESE EXPERIMENTS WILL CLARIFY UNDER WHAT CIRCUMSTANCES OHC/VHSS PRODUCE IDPS AND TO WHAT EXTENT THEY CONTRIBUTE TO THE DPOAES COMMONLY RECORDED IN THE EAR CANAL. IF THE PROPOSED EXPERIMENTS ARE SUCCESSFUL, BY PROVIDING A DIRECT PHYSICAL MECHANISM FOR THE GENERATION OF BASAL DPOAES, DECADES OF THEORETICAL MODELS OF DPOAE GENERATION WILL REQUIRE SIGNIFICANT MODIFICATION AND CLINICAL DP-GRAMS CAN BE IMPROVED BY REMOVING THE CONFOUNDING BASAL DPOAE COMPONENTS WITH AN IT.     1

THYROID HORMONE RECEPTOR ??1 AGONIST THERAPY FOR THE TREATMENT OF BONE MARROW ADIPOSITY IN AGING AND OBESITY

ROLE OF DARC-CHEMOKINE INTERACTION IN THE TRAFFICKING OF OSTEOCLAST PRECURSORS

REGULATION OF BONE FORMATION BY EPHRIN B1 SIGNALING PATHWAYS

DEVELOPMENT OF SMALL MOLECULAR WEIGHT INHIBITORS OF LRRK1 FOR TREATMENT OF OSTEOPOROSIS.

MECHANISMS OF LRRK1 REGULATION OF OSTEOCLAST FUNCTION

A NOVEL MICROVESICLE-BASED THERAPEUTIC STRATEGY OF OSTEOARTHRITIS

LOCAL BLOCKADE OF CCL21 AND CXCL13 SIGNALING AS A NEW STRATEGY TO PREVENT AND TREAT OSTEOARTHRITIS

CHEMOKINE-BASED THERAPY FOR POST-TRAUMATIC OSTEOARTHRITIS

TRANSGENIC APPROACHES TO EVALUTE IGF-1 ROLE IN PEAK BMD

ROLE OF IGF-1 AND ESTROGEN IN SKELETAL ANABOLIC RESPONSE TO LOADING

IDENTIFICATION OF GENDER SPECIFIC BMD CANDIDATE GENE IN CHROMOSOME 1

ROLE OF CHEMOKINE RECEPTOR 3 (CCR3) IN OSTEOARTHRITIS DEVELOPMENT AND TREATMENT

DEVELOPMENT AND CHARACTERIZATION OF A NOVEL STRATEGY TO ENHANCE DELIVERY OF STEM CELLS TO IMPROVE HEALING IN TRAUMATIC MUSCULOSKELETAL INJURIES

SKELETAL REPAIR

MICRORNA, ANGIOGENESIS, AND SKELETAL ANABOLIC RESPONSE TO MECHANICAL STRAIN

"TEST OF FEASIBILITY OF A NOVEL BAX SIRNA-BASED THERAPEUTIC STRATEGY FOR POST-TRAUMATIC OSTEOARTHRITIS"

MECHANISMS OF PORPHYROMONAS GINGIVALIS SIALOGLYCOPROTEASES IN VIRULENCE AND HOST INTERACTIONS

ROLE OF THE AUDITORY EFFERENT SYSTEM IN AUDITORY PERCEPTUAL LEARNING

MECHANICS OF HEARING WORKSHOP 2020