Legacy Emanuel Hospital & Health Center

IOP-RELATED FORCE AND FAILURE IN THE OPTIC NERVE HEAD

OPTIC NERVE HEAD SDOCT IMAGING IN GLAUCOMA

FUNCTIONAL TESTING FOR GLAUCOMA

DYNAMIC AND STATIC AUTOREGULATION IMPAIRMENT IN THE OPTIC NERVE HEAD OF GLAUCOMA

COCAINE, PARVALBUMIN, AND PERINEURONAL NETS - PROJECT SUMMARY/ABSTRACT COCAINE USE DISORDER REMAINS A PREVALENT PROBLEM WITH NO FDA-APPROVED TREATMENT AND PROFOUND SOCIETAL CONSEQUENCES. COCAINE-ASSOCIATED MEMORIES ARE STRONG AND RESISTANT TO MODIFICATION BUT ARE THE BASIS OF RELAPSE IN MANY INDIVIDUALS. OUR LONG-TERM GOAL IS TO DIMINISH COCAINE-ASSOCIATED MEMORIES TO REDUCE DRUG RELAPSE. THE SELF-ADMINISTRATION MODEL IN RODENTS BEST REPRODUCES STRONG COCAINE-ASSOCIATED MEMORY. WE HAVE FOUND THAT THE REMOVAL OF PERINEURONAL NETS (PNNS) IN THE RAT MEDIAL PREFRONTAL CORTEX (MPFC) DISRUPTS COCAINE SELF-ADMINISTRATION MEMORIES BY INTERFERING WITH RECONSOLIDATION OF THESE MEMORIES. PNNS FORM MAINLY AROUND PARVALBUMIN (PV)-CONTAINING, FAST SPIKING INTERNEURONS THAT POWERFULLY REGULATE MPFC OUTPUT, AND MPFC OUTPUT IS WELL KNOWN TO CONTROL DRUG-SEEKING BEHAVIOR IN BOTH ANIMALS AND HUMANS. PV NEURONS MAINTAIN CORTICAL EXCITATORY:INHIBITORY BALANCE AND CONTRIBUTE TO THETA AND GAMMA OSCILLATIONS VITAL FOR COMMUNICATION ACROSS BRAIN REGIONS, YET ALMOST NOTHING IS KNOWN ABOUT HOW MPFC PV NEURONS CONTRIBUTE TO COCAINE MEMORY RECONSOLIDATION. OUR PRELIMINARY DATA SHOW THAT PNN REMOVAL IN THE MPFC: (1) DECREASES PV NEURON FIRING AND INCREASES EXCITABILITY OF PYRAMIDAL CELLS IN DRUG-NAÏVE RATS; (2) PROFOUNDLY DISRUPTS THE RECONSOLIDATION OF A SELF-ADMINISTRATION COCAINE MEMORY, INCLUDING CUE-INDUCED REINSTATEMENT AND PROGRESSIVE RATIO RESPONDING; AND (3) DISRUPTS THE SYNCHRONY OF THETA AND GAMMA OSCILLATIONS WITHIN THE MPFC AND BETWEEN THE MPFC AND HIPPOCAMPUS IN RESPONSE TO A COCAINE CUE. THESE FINDINGS ARE SIGNIFICANT BECAUSE THEY ARE EXPECTED TO GIVE NOVEL INSIGHTS INTO BRAIN OSCILLATORY PATTERNS THAT MAY SIGNIFY DISRUPTED COCAINE MEMORY AND HOW TO MODIFY THESE PERSISTENT DRUG-ASSOCIATED MEMORIES. WE HYPOTHESIZE THAT PNNS ALLOW PV NEURONS TO STABILIZE AND MAINTAIN COCAINE MEMORIES AND THAT, WITHOUT PNNS, THESE MEMORIES CAN BE DESTABILIZED AND PROFOUNDLY DISRUPTED. WE WILL USE PV-CRE KNOCK-IN RATS CROSSED WITH TDTOMATO KNOCK-IN RATS THROUGHOUT TO DETERMINE IN AIM 1 HOW PNN REMOVAL ALTERS MPFC PV NEURON FUNCTION AND IN AIM 2 HOW PNN REMOVAL ALTERS MPFC CIRCUIT FUNCTION DURING COCAINE MEMORY RECONSOLIDATION. IN AIM 3, WE WILL ASSESS TWO MECHANISTIC PATHWAYS BY WHICH PNN REMOVAL BLOCKS RECONSOLIDATION, INCLUDING CRE-DEPENDENT, SPECIFIC SUPPRESSION OF PNNS AND CRE-DEPENDENT INHIBITION OF PV NEURON ACTIVITY WITH GI-DREADDS. WE WILL USE BOTH SLICE AND IN VIVO ELECTROPHYSIOLOGY, TRANSCRIPTOMICS, TRACT TRACING, IMMUNOHISTOCHEMISTRY, MOLECULAR, AND CHEMOGENETIC APPROACHES TO IDENTIFY KEY FACTORS IN PV NEURON-MEDIATED CONTROL OF COCAINE-SEEKING BEHAVIOR DURING COCAINE MEMORY RECONSOLIDATION. OUR STUDIES ARE EXPECTED TO GENERATE SIGNIFICANT ADVANCES IN UNDERSTANDING HOW TO DIMINISH POWERFUL MEMORIES THAT DRIVE COCAINE-SEEKING BEHAVIOR.

FUNCTIONAL TESTING AND QUALITY OF LIFE IN GLAUCOMA - PROJECT SUMMARY / ABSTRACT THE GOAL OF CLINICAL MANAGEMENT IN EYE CARE IS TO PROTECT PATIENTS’ VISION AND CONSEQUENT QUALITY OF LIFE. YET, THE IMPACT OF VISION LOSS ON AN INDIVIDUAL’S QUALITY OF LIFE DEPENDS NOT ONLY ON ITS SEVERITY, BUT ALSO ON ITS LOCATION WITHIN THE VISUAL FIELD. SOME TASKS ARE PREDOMINANTLY IMPACTED BY CENTRAL VISUAL FIELD LOSS, WHILE OTHERS RELY MORE ON DIFFERING REGIONS OF THE PERIPHERAL VISUAL FIELD. THUS, TWO INDIVIDUALS WITH THE SAME DISEASE SEVERITY COULD HAVE VERY DIFFERENT EXPERIENCES OF THAT LOSS. THIS IS PARTICULARLY TRUE FOR GLAUCOMA, WHICH CAUSES LOCALIZED LOSS IN LOCATIONS THAT CAN DIFFER GREATLY BETWEEN INDIVIDUALS. IN THIS PROJECT, WE WILL DETERMINE THE REGIONS OF THE VISUAL FIELD THAT MOST INFLUENCE DIFFERENT ASPECTS OF QUALITY OF LIFE. WE WILL DERIVE QUANTITATIVE METRICS OF THE LIKELY REAL- WORLD EFFECTS OF AN INDIVIDUAL PATIENT’S VISUAL FIELD DEFECT THAT CAN BE OBTAINED WITHOUT RELYING ON TIME-CONSUMING AND VARIABLE QUESTIONNAIRES. THESE PATIENT-CENTERED METRICS CAN AID CLINICIANS IN PRIORITIZING CARE AND CHOOSING APPROPRIATE MANAGEMENT STRATEGIES; AND IN EXPLAINING TO AN INDIVIDUAL PATIENT WHAT THE LIKELY CONSEQUENCES ARE OF THEIR DISEASE, BOTH AS MOTIVATION TO MAINTAIN MEDICATION ADHERENCE AND SO THAT THEY CAN MAKE NECESSARY ADJUSTMENTS TO THEIR ACTIVITIES OF DAILY LIVING. IN AIM 1, WE WILL DERIVE INDICES PREDICTING THE EFFECT OF AN INDIVIDUAL’S VISUAL FIELD LOSS ON DIFFERENT PATIENT-REPORTED OUTCOME MEASURES, BY PARAMETERIZING RESULTS FROM CLINICAL STANDARD AUTOMATED PERIMETRY, TO MAXIMIZE CORRELATIONS WITH RESULTS OF PATIENT QUESTIONNAIRES FROM FOUR LARGE STUDIES OF OCULAR HYPERTENSION AND GLAUCOMA. IN AIM 2, WE WILL USE SIMILAR ANALYSES TO PREDICT THE IMPACT ON VISUAL SEARCH AS MEASURED BY A CUSTOM-WRITTEN TEST, PERFORMED ON A TABLET COMPUTER IN GLAUCOMA CLINIC WAITING ROOMS AND TESTING ROOMS. IN AIM 3, WE WILL PREDICT THE IMPACT OF AN INDIVIDUAL’S VISUAL FIELD LOSS ON THE VISUAL CONTRIBUTION TO BALANCE AND SUBSEQUENT RISK OF FALLING, USING OBJECTIVE MEASUREMENTS OF BALANCE IN BOTH HIGH AND LOW AMBIENT LIGHT SETTINGS. OVERALL, THE PROJECT WILL PROVIDE SUBSTANTIAL ADVANCES IN OUR UNDERSTANDING OF THE EFFECTS OF LOCALIZED VISUAL FIELD LOSS AS CAUSED BY GLAUCOMA, AND PROVIDE INVALUABLE NEW INFORMATION FOR CLINICIANS AND PATIENTS.

ADENOSINE AND SCHIZOPHRENIA: MECHANISMS AND THERAPIES

PROMOTING RESILIENCE AND MENTAL HEALTH AMONG HEALTH PROFESSIONAL WORKFORCE

ADVANCING OCT EVALUATION TO REVEAL EARLY-STAGE CHANGES IN GLAUCOMA

OPTIMIZING LIPID NANOPARTICLES FOR RETINAL GENE EDITING IN THE NHP - PROJECT SUMMARY INHERITED RETINAL DYSTROPHIES (IRDS) ARE A GROUP OF GENETICALLY AND CLINICALLY HETEROGENOUS DISEASES, INHERITED IN AN AUTOSOMAL DOMINANT, RECESSIVE, OR X-LINKED PATTERN. WITH AN ESTIMATED INCIDENCE OF 1:2000-1:3000, IRDS ARE THE LEADING CAUSE OF VISION LOSS IN PERSONS AGED 15 TO 45. TO DATE, MUTATIONS IN 280 DISTINCT GENES HAVE BEEN ASSOCIATED WITH RETINAL PATHOLOGY. GENE AUGMENTATION, EDITING, AND SILENCING ARE THE MOST ATTRACTIVE THERAPEUTIC STRATEGIES FOR THESE PATIENTS AS THEY CORRECT THE CAUSATIVE GENOMIC MALFUNCTION. CURRENTLY, THERE IS ONLY ONE FDA APPROVED GENE AUGMENTATION THERAPY FOR ONE IRD IN THIS LARGE FAMILY OF RETINAL DEGENERATIONS. OUR LONG-TERM GOAL IS TO GENERATE NOVEL GENE EDITING PLATFORMS FOR IRDS. THE MOST CLINICALLY ADVANCED GENE EDITING THERAPEUTIC FOR RETINAL DEGENERATION IS EDIT-101, WHICH USES A VIRAL VECTOR (AAV) TO DELIVER THE CAS9 ENDONUCLEASE AND TWO GUIDE RNAS THAT TARGET THE CEP290 GENE IN LEBER CONGENITAL AMAUROSIS TYPE 10 PATIENTS. WHILE THIS IS THE FIRST IN-VIVO CRISPR/CAS9 CLINICAL TRIAL UNDERWAY TO TREAT RETINAL DEGENERATION, THE TRIAL IS CURRENTLY PAUSED, SUGGESTING THERE IS ROOM FOR IMPROVEMENT IN THE EFFICACY OF THIS PRODUCT EITHER THROUGH MODULATING THE GENE EDITING TOOLS, OR THE DELIVERY PLATFORM. DELIVERING THE CAS9 ENDONUCLEASE IN THE FORM OF MRNA, WHICH LEADS TO TRANSIENT, ROBUST PROTEIN EXPRESSION, WOULD MITIGATE SAFETY CONCERNS ASSOCIATED WITH AAV-MEDIATED CAS9. THESE SAFETY CONCERNS INCLUDE PERSISTENT EXPRESSION OF CAS9 ENDONUCLEASE AND AAV INTEGRATION INTO THE CAS9-INDUCED DOUBLE STRAND BREAKS. LIPID-BASED NANOPARTICLES (LNPS) ARE THE MOST CLINICALLY ADVANCED NON-VIRAL PLATFORM THAT CAN ENCAPSULATE MRNA AND DELIVER GENOME EDITORS. SYSTEMIC ADMINISTRATION OF LNPS, THAT ENCAPSULATE CAS9 MRNA AND A GUIDE RNA TARGETING TRANSTHYRETIN (TTR), HAS LED TO A 90% REDUCTION IN MISFOLDED TTR PROTEIN IN AMYLOIDOSIS PATIENTS. TO TRANSLATE THESE THERAPEUTIC GAINS OBSERVED IN THE LIVER TO THE RETINA, WE FIRST MEASURED GENE EDITING EVENTS FOLLOWING SUBRETINAL ADMINISTRATION OF AN LNP ENCAPSULATING CAS9 MRNA AND GUIDE RNA IN AI9 MICE. IN THIS PROPOSAL, WE SHOW SIGNIFICANT LNP- MEDIATED GENE EDITING IN THE MURINE RETINA. ADDITIONALLY, WE WERE ONE OF THE FIRST GROUPS TO DELIVER LNPS TO THE SUBRETINAL SPACE OF RHESUS MACAQUES AND DEMONSTRATE THEIR ABILITY TO TRANSFECT PHOTORECEPTORS. TO ADVANCE THE DEVELOPMENT OF LNP-MEDIATED GENE EDITING THERAPIES FOR IRDS, THERE ARE THREE CRITICAL GAPS OF KNOWLEDGE WE PROPOSE TO ADDRESS IN THE MOST CLINICALLY RELEVANT MODEL, THE NONHUMAN PRIMATE (NHP): 1) DETERMINE WHICH PHYSIOCHEMICAL FEATURES OF LNPS FACILITATE PHOTORECEPTOR EXPRESSION OF GENE EDITORS, 2) EVALUATE THE IMMUNOGENICITY OF LNPS IN THE SUBRETINAL SPACE, AND 3) QUANTIFY IN-VIVO GENE EDITING EFFICIENCY IN THE PHOTORECEPTORS. SUCCESSFUL COMPLETION OF THESE AIMS WILL GENERATE NOVEL LNP PLATFORMS THAT MEDIATE THE EXPRESSION OF GENE EDITORS IN NHP PHOTORECEPTORS. THIS WILL LEAD TO AN UNDERSTANDING OF IN-VIVO GENE EDITING IN LARGE ANIMALS THAT CAN BE TRANSLATED TO SPECIFIC IRD MUTATIONS. OVERALL, THESE STUDIES WILL ADVANCE THE DEVELOPMENT OF LNP GENE EDITING THERAPEUTICS FOR IRDS.

PERINEURONAL NETS AND COCAINE-ASSOCIATED MEMORIES

PREDICTING THE RATE OF PROGRESSION IN GLAUCOMA

BLOOD FLOW AND HEMODYNAMICS IN GLAUCOMA

GLYCINE AUGMENTATION THERAPY FOR THE TREATMENT OF EPILEPSY

AXONAL CYTOSKELETAL CHANGES IN EXPERIMENTAL GLAUCOMA

ASTROCYTE DYSFUNCTION IN EPILEPTOGENESIS: THE ROLE OF ADENOSINE

REGULATION OF DIURNAL RHYTHMS IN PARVALBUMIN AND PERINEURONAL NET FUNCTION - ABSTRACT MEMORY RETRIEVAL REQUIRES OPTIMAL FUNCTIONING FOR AN ORGANISM’S SURVIVAL AND VARIES WITH THE TIME OF DAY. THE BIOLOGICAL CLOCK BIASES OUTPUT OF BRAIN CIRCUITRY TO COORDINATE BEHAVIORS ACROSS THE LIGHT/DARK CYCLE. GABAERGIC NEURONS ALIGN CIRCUIT ACTIVITY TO GATE DAILY RHYTHMS THROUGH EXPRESSION OF LOCAL CIRCADIAN-ASSOCIATED CLOCK GENES. PARVALBUMIN (PV) GABAERGIC NEURONS POWERFULLY MODIFY CIRCUITS NEEDED FOR MEMORY RETRIEVAL, BUT THE EXTENT TO WHICH PV NEURONS REGULATE DAILY RHYTHMS IN RETRIEVAL IS UNKNOWN. THIS INFORMATION IS IMPORTANT BECAUSE DESYNCHRONY BETWEEN THE 24 HR LIGHT CYCLE AND ENDOGENOUS CIRCADIAN RHYTHMS LEADS TO COGNITIVE DEFICITS IN SHIFT WORKERS, THOSE WITH JET LAG, AGED INDIVIDUALS, AND IN THOSE WITH NEUROLOGICAL DISORDERS IN WHICH CIRCADIAN REGULATION OF THE BIOLOGICAL CLOCK IS IMPAIRED. IN THE MEDIAL PREFRONTAL CORTEX (MPFC), THE FOCUS OF THESE STUDIES, MOST PV NEURONS ARE ENWRAPPED IN STRUCTURES CALLED PERINEURONAL NETS (PNNS), WHICH RESTRICT PLASTICITY IN ADULTHOOD AND ARE VITAL FOR PRECISE FIRING OF PV NEURONS. WE DISCOVERED THAT THE EXPRESSION OF PNNS AND PV EXHIBIT A DIURNAL PATTERN IN THE RAT MPFC, AND PROPOSE THAT THIS DIURNAL PATTERN IS A MAJOR FACTOR DRIVING DIURNAL DIFFERENCES IN MEMORY RETRIEVAL. MOREOVER, WE PROPOSE THAT THE DIURNAL PATTERN IN PNNS IS COORDINATED BY ORTHODENTICLE HOMEOBOX 2 (OTX2), WHICH MAINTAINS PNNS AND EXHIBITS A SIMILAR DIURNAL PATTERN AS PNNS. OTX2 APPEARS TO BIND TO PROMOTER-PROXIMAL REGIONS OF THE CLOCK GENES CLOCK, PER1, AND PER2 AND THUS MAY SERVE AS A MAJOR INTEGRATOR OF ACTIVITY-DEPENDENT RHYTHMS THAT COORDINATE WITH THESE CLOCK PROTEINS. CONSISTENT WITH THIS, WE SHOW THAT PNN REMOVAL DISRUPTS THE DIURNAL RHYTHM OF PER1 PROTEIN LEVELS IN PV NEURONS. TOGETHER, PRIOR WORK AND OUR STUDIES SHOW THAT PNNS INFLUENCE THE CORE CLOCK, WHICH CAN POTENTLY INFLUENCE CIRCUIT FUNCTION DURING MEMORY RETRIEVAL. WE HYPOTHESIZE THAT PNNS SURROUNDING PV NEURONS IN THE MPFC ARE A MAJOR CONTRIBUTOR TO DIURNAL PATTERNS OF MEMORY RETRIEVAL THROUGH REGULATION OF CLOCK GENES. OUR STUDIES WILL DEFINE HOW DIURNAL FLUCTUATIONS IN PNNS AROUND PV NEURONS ALTER CIRCADIAN GENES AND PV NEURON FUNCTION IN THE MPFC, AND WHETHER THESE DIURNAL FLUCTUATIONS UNDERLIE DIURNAL DIFFERENCES IN MEMORY RETRIEVAL. CONVERSELY, WE WILL DETERMINE HOW MANIPULATION OF THE CLOCK GENE BMAL1 ALTERS PNNS, PV NEURON FUNCTION, AND MEMORY RETRIEVAL. WE WILL USE BEHAVIOR, INNOVATIVE MOLECULAR APPROACHES, AND IN VITRO AND IN VIVO ELECTROPHYSIOLOGY TO ADDRESS THE FOLLOWING THREE SPECIFIC AIMS: AIM 1) DETERMINE HOW PNNS IN THE MPFC MODULATE RHYTHMICITY OF PV NEURON CLOCK GENES, PV NEURON FUNCTION, AND MEMORY RETRIEVAL.; AIM 2) DETERMINE WHETHER THE CORE CLOCK IN MPFC PV NEURONS REGULATES RHYTHMICITY OF PNN, PV NEURON FUNCTION, AND MEMORY RETRIEVAL; AND AIM 3) DEFINE DIURNAL CHANGES IN OSCILLATORY COMMUNICATION BETWEEN THE MPFC, BASOLATERAL AMYGDALA, AND HIPPOCAMPUS. UNDERSTANDING HOW ENDOGENOUS DAILY RHYTHMS IN PNNS AND THEIR PV INTERNEURONS CONTRIBUTE TO MEMORY RETRIEVAL IS EXPECTED TO FACILITATE TREATMENT OF COGNITIVE IMPAIRMENTS IN THOSE WITH CIRCADIAN RHYTHM DESYNCHRONY.

ADENOSINE-RELEASING BRAIN IMPLANTS FOR EPILEPSY THERAPY

TRANSIENT DELIVERY OF ADENOSINE AS A NOVEL THERAPY TO PREVENT EPILEPTOGENESIS

RACIAL VARIATIONS IN OPTIC NERVE HEAD STRUCTURE AND BIOMECHANICS

ROLE OF CB1 RECEPTORS IN OPIOID TOLERANCE DURING PAIN

ADENOSINE KINASE ANTISENSE GENE THERAPY FOR TEMPORAL LOBE EPILEPSY.

PRIMARY C NOCICEPTORS AND C SYMPATHETICS IN CRPS

MOLECULAR MECHANISMS OF SEIZURE INDUCED BRAIN INJURY

ACID-SENSING ION CHANNELS AND ISCHEMIC BRAIN INJURY

NEUROPROTECTION BY NOVEL REGULATORS OF MGLUR SIGNALING

MOLECULAR BASIS OF VESTIBULAR EFFERENT FUNCTION

80 YEARS AND OLDER VISION & HEARING IMPORTANT PERSONS PROJECT (80VIP) - PROJECT SUMMARY/ABSTRACT PREVIOUS PREVALENCE STUDIES INCLUDE ONLY SMALL AND INFREQUENT ESTIMATES OF VISION, HEARING, BALANCE LOSS OR DUAL SENSORY LOSS (DSL) IN OLDER ADULTS OVER AGED 80 YEARS, WHICH CREATES A LARGE GAP IN KNOWLEDGE IN THIS IMPORTANT AGE GROUP. THIS AGE GROUP WILL INCREASE BY 600% IN THE NEXT 30 YEARS, AN INCREASE FASTER THAN ANY OTHER AGE STRATA, OR MINORITY GROUP. MANY OLDER PATIENTS ADMITTED INTO INSTITUTIONALIZED CARE HAVE HIGH PROPORTIONS OF UNTREATED VL/HL/DSL. UNFORTUNATELY, LITTLE DATA EXISTS ON THE EFFECTIVENESS OF TREATING VL/HL/DSL TO DECREASE MORBIDITY, INCREASE QUALITY OF LIFE, AND DECREASE CAREGIVER BURDEN AND COST IN THIS SUSCEPTIBLE AGE GROUP. THIS DEMONSTRATES A NEED TO UNDERSTAND THE PREVALENCE AND IMPACT OF UNDIAGNOSED VL/HL/DSL IN COMMUNITY DWELLING OLDER ADULTS. AGE-RELATED HEARING AND VISION IMPAIRMENT WILL EACH RANK WITHIN THE TOP 10 BURDENS OF DISEASE IN MIDDLE- AND HIGH-INCOME COUNTRIES IN THE NEXT 20 YEARS. THIS EVALUATION OF OLDER PERSONS FITS WITH THE NATIONAL INSTITUTES OF HEALTH'S NEW "INCLUSION ACROSS THE LIFESPAN" POLICY THAT WAS IMPLEMENTED IN JANUARY 2019. THE R34 PLANNING GRANT IS TO SUPPORT THE DEVELOPMENT OF A DETAILED INFRASTRUCTURE FOR A FUTURE ‘80 YEARS AND OLDER VISION & HEARING IMPORTANT PERSONS PROJECT (80VIP)’ UNDER THE UG1 COOPERATIVE AGREEMENT FUNDING MECHANISM. THIS SPECIAL POPULATION (AGE >80 YEARS) IS RARELY INCLUDED IN POPULATION-BASED PREVALENCE SURVEYS OR CLINICAL TRIALS, AND MAY REQUIRE MORE EFFORT, OR NEW METHODS TO RECRUIT AND ENROLL PARTICIPANTS WHEN COMPARED TO PREVIOUS STUDIES. WE WILL ALSO DEVELOP A COMPREHENSIVE MANUAL OF PROCEDURES, WHICH INCLUDES STANDARDS FOR COLLECTING OCULAR AND BIOMETRIC DATA, INCLUDES NEW INSTRUMENTATION, AND ALLOWS COMPARISONS WITH PREVIOUS GROUNDBREAKING PREVALENCE SURVEYS. WE WILL ALSO EVALUATE THE BURDEN, FEASIBILITY, AND SUITABILITY OF THE PROTOCOL FROM THE PERSPECTIVE OF KEY STAKEHOLDERS, WHICH INCREASES THE LIKELIHOOD OF A SUCCESSFULLY TRANSITION INTO A LARGER UG1 STUDY; AND WE WILL DEVELOP A STATISTICAL ANALYSIS PLAN THAT ADDRESSES ALL OF THE PROPOSED FUTURE HYPOTHESES. THE STUDY TEAM HAS THE EXPERTISE TO CONDUCT THIS PROPOSAL, AND MOVE THIS PLANNING GRANT PROPOSAL TOWARD A SUCCESSFUL UG1 APPLICATION. IN THE FUTURE, THE EXPERIENCES AND DATA FROM THIS PROPOSAL WILL HELP PLAN HEALTH RESOURCES REQUIREMENTS IN THE FUTURE, AND INTERVENTIONS TO AUGMENT HEALTHY LIVING, PREVENT MORBIDITY SUCH AS INSTITUTIONALIZED CARE, AND REDUCE THE HIGH ECONOMIC COSTS OF VISION AND HEARING LOSS.

IDENTIFYING PREFRONTAL CORTEX NEURAL ENSEMBLES IN COCAINE-ASSOCIATED MEMORIES

ASTROCYTE-MEDIATED BLOOD FLOW AUTOREGULATION AS A DISEASE MECHANISM IN GLAUCOMA

NOVEL CORRELATIONS IN CELLULAR, MOLECULAR AND STRUCTURAL ALTERATIONS IN EXPERIMENTAL JUVENILE MYOPIA - SUMMARY MYOPIA IS A COMPLEX AND MULTIGENIC REFRACTIVE DISORDER THAT DOES NOT ONLY IMPAIR VISION BUT ALSO INCREASES THE RISK FACTOR TO DEVELOP IRREVERSIBLE BLINDING DISEASES LATER IN LIFE. WHILE SCLERAL REMODELING AND DECREASED CONNECTIVE TISSUE SYNTHESIS HAVE BEEN SHOWN TO UNDERLY THE EXCESSIVE AXIAL ELONGATION IN MYOPIA, THE SPECIFICS OF MICRO- AND MACRO-LEVEL INTERACTIONS REMAIN ELUSIVE. IN THIS PROPOSAL, WE PLAN TO USE TREE SHREW MODEL OF MYOPIA. WE HYPOTHESIZE THAT INFILTRATION OF PERIPHERAL IMMUNE CELLS, INCLUDING MYELOID CELLS CORRELATE WITH MYELIN ALTERATIONS, AXONAL/NEURONAL DAMAGE ULTIMATELY LEADING TO MYOPIA DEVELOPMENT AND PROGRESSION. WE PLAN TO CONDUCT THIS STUDY IN TWO SPECIFIC AIMS. FIRST, WE WILL ASSESS ALTERATIONS IN AXONAL HEALTH, MYELIN AND IMMUNE CELL INFILTRATION IN THE OPTIC NERVE HEAD (ONH) USING IMMUNOHISTOCHEMICAL AND NOVEL SPATIAL PROTEIN PROFILING BY NANOSTRING IN MODERATE AND HIGH MYOPIA. NEXT, WE PLAN TO CORRELATE THESE MICRO-LEVEL ALTERATIONS WITH TISSUE LEVEL ALTERATIONS FROM OPTICAL COHERENT TOMOGRAPHY (OCT) IMAGES OF THE ONH. WE PREDICT THAT ALTERATIONS IN AXONAL HEALTH, MYELIN, AND INFLAMMATION WILL COINCIDE WITH THE ONH REMODELING VISUALIZED BY OCT IN THE TREE SHREW MODEL OF MYOPIA. THIS STUDY WILL BRIDGE THE GAP IN OUR UNDERSTANDING OF LOCALIZED MOLECULAR MECHANISMS AND PATHOGENESIS INVOLVED IN OCULAR REMODELING DURING MYOPIA DEVELOPMENT. IT WILL ULTIMATELY OPEN A WHOLE NEW AVENUE TOWARDS DESIGNING AND DEVELOPING NOVEL TREATMENT STRATEGIES THAT COUNTERACT THE DRIVING FORCES OF MYOPIA DEVELOPMENT AND PROGRESSION.

ACID-SENSING CHANNELS AS NOVEL TARGET FOR BRAIN ISCHEMIA

IMAGING RETINAL ASTROCYTES, GANGLION CELLS AND AXONAL TRANSPORT IN VIVO

ADENOSINE KINASE AS THERAPEUTIC TARGET TO INDUCE AND MAINTAIN ISCHEMIC TOLERANCE

ADENOSINE KINASE AS NOVEL THERAPEUTIC TARGET TO PREVENT ACQUIRED EPILEPSY

A NOVEL CATION CHANNEL IN EXCITATORY NEURONAL INJURY

BRAIN ISCHEMIA ATTENUATES NEUROPEPTIDE BIOSYNTHESIS

SURVIVAL AND INJURY OUTCOME AFTER TBI: INFLUENCE OF PRE- AND POST-EXPOSURE TO CAFFEINE

CONGRESSIONALLY-MANDATED HEALTH INFORMATION TECHNOLOGY GRANTS