Philadelphia College Of Osteopathic Medicine

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND- IHES

CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND - IHES

DETERMINANTS OF CARDIAC THIN FILAMENT REGULATION

FINANCIAL AID GRANTS TO GRADUATE STUDENTS WITH FINANCIAL NEED ASSOCIATED WITH THE CORONAVIRUS

DEFINING THE ROLE OF CD38 AND ITS POTENTIAL AS A THERAPEUTIC TARGET IN SBMA - PROJECT SUMMARY: DEFINING THE ROLE OF CD38 AND ITS POTENTIAL AS A THERAPEUTIC TARGET IN SBMA SPINAL AND BULBAR MUSCULAR ATROPHY (SBMA) IS A SLOWLY PROGRESSIVE, X-LINKED NEUROMUSCULAR DISEASE AFFECTING MEN, AND IS CAUSED BY A POLYGLUTAMINE EXPANSION WITHIN THE ANDROGEN RECEPTOR (AR). WITH NO DISEASE-MODIFYING THERAPY, IDENTIFYING POTENTIAL THERAPEUTIC INTERVENTIONS FOR THIS PATIENT POPULATION IS PRESSING. MITOCHONDRIAL AND METABOLIC DYSFUNCTIONS ARE CRITICAL TO PATHOGENESIS. SBMA PATIENTS SUFFER SEVERE FATIGABILITY OF THEIR MUSCULATURE, BUT THE FIELD HAS YET TO INTERROGATE METABOLISM IN SBMA PATIENT SKELETAL MUSCLE. OUR STUDIES OUTLINED HEREIN WILL FILL THIS GAP BY USING STATE OF THE ART STEM CELL TECHNOLOGY PAIRED WITH CRISPR-CORRECTED ISOGENIC CONTROLS TO INVESTIGATE METABOLIC ALTERATIONS IN SBMA PATIENT-DERIVED IPSCS DIFFERENTIATED INTO SKELETAL MUSCLES. ONE OF THE ESSENTIAL CO-FACTORS UTILIZED TO SUSTAIN ENERGY BY POWERING MITOCHONDRIA AND OVERALL METABOLISM, NAD+, IS SUBSTANTIALLY DIMINISHED IN SKELETAL MUSCLE OF MICE MODELING SBMA. THE MECHANISM(S) BY WHICH NAD+ IS REDUCED AND HOW TO RECOVER IT HAS BEEN ELUSIVE TO THE FIELD. CLUSTER OF DIFFERENTIATION 38 (CD38) IS AN ECTO-ENZYME THAT IS EXPRESSED BY IMMUNE CELLS, AS WELL AS OTHER TISSUES INCLUDING SKELETAL MUSCLE FIBERS, AND CD38 EXPRESSION PATTERNS IN MICE ARE SIMILAR TO HUMANS. CD38 IS PRIMARILY A NAD+ GLYCOHYDROLASE, AND IT IS THE MAIN NAD+ CATABOLIC ENZYME. WE PERFORMED METABOLOMICS ANALYSES OF SKELETAL MUSCLE SAMPLES FROM TRANSGENIC MICE MODELING SBMA (AR100Q) AND IT REVEALED A 2-FOLD INCREASE OF ONE THE PRODUCTS OF CD38’S HYDROLYSIS OF NAD+, ADPR, OVER WILD-TYPE MICE. PHARMACOLOGIC INHIBITION OF CD38 REDUCED ADPR AND RESTORED NAD+ TO LEVELS SIMILAR TO THOSE OF WILD-TYPE MICE. THESE DATA SUGGEST THAT HYPERACTIVITY OF CD38 MAY BE ONE OF THE MAJOR MECHANISMS BY WHICH NAD+ IS DEPLETED AND THAT INHIBITING ITS ACTIVITY MAY BE A MEANS TO RESTORE NAD+ IN SBMA. CD38 INHIBITION ALSO ENHANCED GLYCOLYSIS, CORRECTED TCA CYCLE ACTIVITY, AND IMPROVED MOTOR FUNCTION OF THESE SBMA MICE. IN THIS PROPOSAL WE WILL FURTHER INTERROGATE THE ROLE OF CD38 IN SBMA PATHOGENESIS IN TWO MOUSE MODELS OF SBMA (AR100Q AND AR113Q (KNOCK IN)), AND WE WILL TEST MORE CLINICALLY TRANSLATIONAL CD38 INHIBITORS. CD38 ACTIVITY IN EITHER TISSUE RESIDENT IMMUNE CELLS OR SKELETAL MUSCLE FIBERS CAN IMPACT NAD+ AND METABOLISM IN TISSUE. THUS, WE HAVE OUTLINED STUDIES IN MICE TO EVALUATE INFLAMMATION IN SBMA AND DETERMINE THE RELATIVE CONTRIBUTION OF CD38+ IMMUNE INFILTRATE TO NAD+ DEPLETION IN SKELETAL MUSCLE TISSUE. INVESTIGATIONS USING SKELETAL MUSCLE CULTURES FROM SBMA PATIENTS WILL COMPLEMENT THESE CD38 STUDIES IN MICE. OVERALL OUR PROPOSAL HIGHLIGHTS THE POTENTIAL TO CORRECT METABOLIC AND MOTOR FUNCTION IN SBMA WITHOUT UNTOWARD EFFECTS UPON THE NORMAL FUNCTION OF AR THAT IS CRITICAL FOR MUSCLE FUNCTION. CD38 INHIBITORS ARE IN CLINICAL DEVELOPMENT MY MULTIPLE BIOTECHNOLOGY COMPANIES AND OUR STUDIES HAVE POTENTIAL TO ESTABLISH A RATIONALE FOR FUTURE TRIALS IN SBMA PATIENTS.

PRE-DOCTORAL TRAINING IN PRIMARY CARE

MECHANISMS OF GROWTH PLATE PATTERNING REVEALED BY NATURAL VARIATION IN MAMMALIAN OSSIFICATION

MECHANISMS OF CALCINEURIN ISOFORM-SPECIFICS SIGNALING

EVOLUTION AND DEVELOPMENT OF THE HOMINOID WRIST

IN VIVO AND EX VIVO MECHANISMS RELATED TO ENOS UNCOUPLING DURING REPERFUSION

ANTI-OSTEOGENIC FUNCTIONS OF LIPOCALIN2, AN INNATE IMMUNE PROTEIN, DURING AUTOIMMUNE ARTHRITIS

GENERATION AND CHARACTERIZATION OF A CRE-LOX REGULATED TRANSGENIC ZEBRAFISH MODEL OF SBMA - SPINAL AND BULBAR MUSCULAR ATROPHY (SBMA OR KENNEDY'S DISEASE) IS A SLOWLY PROGRESSIVE, X-LINKED NEUROMUSCULAR DISEASE AFFECTING MEN. IT IS CAUSED BY THE EXPANSION OF A CAG REPEAT WITHIN THE ANDROGEN RECEPTOR (AR) GENE, ENCODING A GLUTAMINE TRACT IN THE PROTEIN. WITH NO CURE OR THERAPY, IDENTIFYING POTENTIAL THERAPEUTIC INTERVENTIONS FOR THIS PATIENT POPULATION IS PRESSING. WE AIM TO CREATE A CRE-INDUCIBLE, LOW COST, AND HIGH-THROUGHPUT MODEL OF SBMA USING ZEBRAFISH. DISCOVERIES MADE FROM ZEBRAFISH RESEARCH ARE HIGHLY TRANSLATABLE TO HUMANS SINCE ZEBRAFISH ARE VERTEBRATES WITH EXTENSIVE STRUCTURAL HOMOLOGY TO HUMAN NEUROANATOMY AND MUSCLE PHYSIOLOGY. MORE SPECIFICALLY FOR SBMA PATIENTS, ZEBRAFISH EXPRESS AN AR THAT IS HIGHLY HOMOLOGOUS IN STRUCTURE AND FUNCTION TO HUMAN AR. CRE-INDUCIBILITY OF THE HUMAN AR TRANSGENE WILL ENABLE THE PRODUCTION OF FOUNDER LINES THAT ARE ABLE TO EXPRESS HIGH LEVELS OF THE TOXIC POLYGLUTAMINE-EXPANDED AR. WE HYPOTHESIZE THIS WILL LEAD TO ROBUST MOTOR DYSFUNCTION IN LARVAL ZEBRAFISH. THESE LARVAL ZEBRAFISH MODELING SBMA WILL BE AMENABLE TO QUICK (OVER 1-2 WEEKS) CHEMICAL AND DRUG LIBRARY SCREENS, OR GENETIC MODIFICATION(S) TO IDENTIFY MODULATORS OF MOTOR FUNCTION. SUCH ASSAYS COULD BE SET UP WITHIN ONLY A FEW DAYS AND AT A VERY LOW COST COMPARED TO SUCH ASSAYS IN RODENT MODELS. MOREOVER, TISSUE SPECIFIC CRE ZEBRAFISH LINES CAN BE CROSSED WITH THESE SBMA ZEBRAFISH IN FUTURE STUDIES TO INVESTIGATE THE RELATIVE ROLE OF MOTOR NEURONS VERSES SKELETAL MUSCLE IN THE ONSET AND PROGRESSION OF SBMA PATHOGENESIS. A BETTER UNDERSTANDING OF THE RELATIVE ROLES OF EACH OF THESE CELL TYPES IN DISEASE WILL SUPPORT CLINICAL TRIAL DESIGN FOR SBMA PATIENTS. FURTHER, BECAUSE SBMA SHARES PROPERTIES WITH OTHER NEURODEGENERATIVE, NEUROMUSCULAR, AND POLYGLUTAMINE DISEASES, THERAPEUTIC TARGETS IDENTIFIED IN THE SBMA ZEBRAFISH MODEL MAY ALSO BE APPLICABLE TO SOME OF THESE OTHER DISORDERS.

GENERATION AND CHARACTERIZATION OF A ZEBRAFISH MODEL OF SBMA

LDS - OSTEOPATHIC MEDICINE - LOAN GRANT WITH FUNDS FOR NEW BUDGET PERIOD

HEALTH CARE AND OTHER FACILITIES

HEALTH CARE AND OTHER FACILITIES

CLOSEOUT DOCUMENT NUMBER

PCL - OSTEOPATHIC MEDICINE - PD CHANGES

RURAL HEALTH OUTREACH SPECIAL INITIATIVE