THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.

Headquarter of

F20000002254

FLORIDA

THE HOSPITAL FOR SPECIAL SURGERY FUND, INC. (FL)

LGHBJMLVD8H3

1YZN4

2025-08-29

HSS FOUNDATION

http://www.hss.edu

THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.

2024-09-02

2002-06-19

1YZN4

Active

Non-Manufacturer

2024-09-02

2029-09-02

2025-08-29

DEONARINE ARJUNE

http://www.hss.edu

W912PQ15P0247

View Award on USAspending website

AWARD

PURCHASE ORDER

90000.00

90000.00

90000.00

Department of Defense

2015-09-17

IGF::CT::IGF HUMAN PERFORMANCE OPTIMIZATION

541690: OTHER SCIENTIFIC AND TECHNICAL CONSULTING SERVICES

Q518: MEDICAL- PHYSICAL MEDICINE/REHABILITATION

NNA15BC03P

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AWARD

PO

16300.00

16300.00

16300.00

National Aeronautics and Space Administration

2015-09-03

IGF::OT::IGF BONE HISTOMORPHOMETRY TO DETERMINE EFFECTS OF RADIATION AND DISUSE ON BONE

541711: RESEARCH AND DEVELOPMENT IN BIOTECHNOLOGY

AB91: R&D- COMMUNITY SERVICE/DEVELOPMENT: OTHER (BASIC RESEARCH)

HHSN264201500101PC

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AWARD

PO

3750.00

3750.00

3750.00

Department of Health and Human Services

2015-07-13

IGF::CL::IGF

811212: COMPUTER AND OFFICE MACHINE REPAIR AND MAINTENANCE

Q301: MEDICAL- LABORATORY TESTING

2024-11-22

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Department of Health and Human Services

MECHANISMS OF INFLAMMATORY OSTEOBLASTOGENESIS AND BONE FORMATION - THE INTEGRITY OF THE ADULT SKELETON IS MAINTAINED BY BALANCED REMODELING BETWEEN OSTEOCLAST-MEDIATED BONE RESORPTION AND OSTEOBLAST/OSTEOCYTE-MEDIATED BONE FORMATION. HOWEVER, EXCESSIVE BONE LOSS BUT LIMITED BONE FORMATION OFTEN OCCUR IN MANY CHRONIC INFLAMMATORY SETTINGS, SUCH AS RHEUMATOID ARTHRITIS (RA) AND PERIODONTITIS. IN CONTRAST TO THE EXTENSIVE STUDIES ON OSTEOCLASTIC BONE RESORPTION, THE DEREGULATED OSTEOBLASTOGENESIS AND DAMAGED BONE FORMATION, ESPECIALLY IN INFLAMMATORY CONDITIONS, ARE MUCH LESS UNDERSTOOD. THERE ARE NO KNOWN EFFECTIVE THERAPIES TO IMPROVE BONE FORMATION IN RA CURRENTLY. WE RECENTLY IDENTIFIED CONSTITUTIVE TYPE-I INTERFERON (IFN-I) RESPONSE ACTIVITY IN OSTEOBLASTS, EVIDENCED BY THE CONSTITUTIVE EXPRESSION OF TYPE I IFN-STIMULATED/RESPONSE GENES (ISGS), WHICH IS A NEWLY RECOGNIZED CELLULAR SIGNATURE OF OSTEOBLASTS. IT IS INTRIGUING THAT OSTEOBLASTS, A NON-TYPICAL IMMUNE CELL TYPE, PRESENT IFN-I RESPONSE SIGNATURE IN THE ABSENCE OF INFECTION. WE FOUND THAT THE CONSTITUTIVE IFN-I RESPONSE PLAYS AN INHIBITORY ROLE IN OSTEOBLAST DIFFERENTIATION AND BONE FORMATION WITH GENETIC EVIDENCE, WHICH UNDERSCORES ITS BIOLOGICAL SIGNIFICANCE IN OSTEOBLASTOGENESIS AND BONE HOMEOSTASIS. ISGS ARE USUALLY THE INDICATORS AND EFFECTORS OF IFN-I PATHWAY/RESPONSE. AMONG THE ISGS, WE IDENTIFIED EIF2AK2 (ENCODING EUKARYOTIC TRANSLATION INITIATION FACTOR 2- ALPHA KINASE 2) AS AN IMPORTANT INHIBITOR OF OSTEOGENESIS. IMPORTANTLY, EIF2AK2 IS A CENTRAL REGULATOR OF IFN-I RESPONSE IN OSTEOBLASTIC INHIBITION. EIF2AK2-/- MICE EXHIBIT SIGNIFICANTLY HIGH BONE MASS WITH PROMINENTLY INCREASED OSTEOBLASTIC BONE FORMATION IN VIVO. OUR DATA INCLUDING RNASEQ RESULTS FURTHER REVEAL A NOVEL PATHWAY MEDIATED BY IFN-I-EIF2AK2-Β-CATENIN IN THE REGULATION OF OSTEOBLASTOGENESIS. MOREOVER, INFLAMMATORY CYTOKINE TNFΑ SIGNIFICANTLY ENHANCES THE CONSTITUTIVE IFN-I RESPONSE IN OSTEOBLASTS, INDICATING A NOVEL MOLECULAR MECHANISM BY WHICH TNFΑ RESTRAINS BONE FORMATION. WE ALSO FOUND A DRASTIC AGING EFFECT OF THE CONSTITUTIVE IFN-I RESPONSE ON BONE MASS. BASED ON OUR PRELIMINARY RESULTS, IN THIS APPLICATION, WE WILL FURTHER 1) INVESTIGATE THE MECHANISMS BY WHICH THE CONSTITUTIVE IFN-I RESPONSE SUPPRESSES OSTEOBLASTOGENESIS; 2) INVESTIGATE HOW THE EFFECTS OF CONSTITUTIVE IFN-I RESPONSE IN OSTEOBLASTS/OSTEOCYTES ON BONE HOMEOSTASIS ARE INFLUENCED BY AGING IN BOTH MALES AND FEMALES; AND 3) INVESTIGATE THE FUNCTIONAL IMPORTANCE OF CONSTITUTIVE IFN-I RESPONSE IN OSTEOBLASTS/OSTEOCYTES IN INFLAMMATORY ARTHRITIC ANIMAL MODELS WITH OSTEOGENIC DEFECTS. SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL SHIFT THE CURRENTLY ESTABLISHED PARADIGM IN IMMUNOLOGY FOR IFN-I RESPONSE TO A NEW PARADIGM IN BONE WITH DISTINCT FUNCTION AND MECHANISMS. IDENTIFICATION OF PREVIOUSLY UNRECOGNIZED MECHANISMS IN OSTEOGENIC INHIBITION WILL PROVIDE A RATIONAL FRAMEWORK FOR DEVELOPING NEW THERAPEUTIC APPROACHES TO ENHANCING OSTEOBLAST/OSTEOCYTE-MEDIATED BONE FORMATION/REPAIR IN SKELETAL DISEASES.

688634.00

0.00

0.00

2024-08-13

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Department of Health and Human Services

TABLET-BASED PHYSICAL ACTIVITY INTERVENTION FOR FRAIL AND PRE-FRAIL OLDER ADULTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS - PROJECT SUMMARY: ALTHOUGH ADULTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) NOW LIVE ROUTINELY TO 50 YEARS OF AGE AND BEYOND, THEIR RISK FOR ADVERSE HEALTH OUTCOMES IS HIGHER COMPARED TO OLDER ADULTS WITHOUT SLE DUE TO THE EFFECTS OF CUMULATIVE END-ORGAN DAMAGE. WHILE FRAILTY IS RECOGNIZED AS AN IMPORTANT MARKER OF VULNERABILITY IN SLE, LIMITED RESEARCH HAS FOCUSED ON TARGETED STRATEGIES TO IMPROVE CLINICALLY RELEVANT OUTCOMES IN FRAIL AND PRE-FRAIL OLDER ADULTS WITH SLE, SUGGESTING AN IMPORTANT UNMET NEED. IN KEEPING WITH STAGE 1 OF THE NATIONAL INSTITUTES OF HEALTH STAGE MODEL FOR BEHAVIORAL INTERVENTION DEVELOPMENT, THE GOAL OF THIS PROJECT IS FIRST TO ADAPT AND THEN TO PILOT TEST A SOCIAL COGNITIVE THEORY-BASED DIGITAL EXERCISE INTERVENTION FOR AGING ADULTS WITH SLE (≥50 YEARS OF AGE) STRATIFIED BY FRAILTY STATUS. THE FITTLE SENIOR SYSTEM (FSS) IS AN EVIDENCE-BASED DIGITAL EXERCISE PLATFORM WITH TEAM-DRIVEN SOCIAL SUPPORT FEATURES CREATED TO PROMOTE PHYSICAL ACTIVITY (PA) IN SEDENTARY OLDER ADULTS WITHOUT COMORBID CONDITIONS. IN THIS STUDY, THE FSS DIGITAL SOFTWARE PLATFORM WILL BE ADAPTED, LEVERAGING AN ESTABLISHED USER-CENTERED DESIGN APPROACH, TO MEET THE NEEDS OF THE SLE POPULATION, RESULTING IN FSS-SLE. MY OVERARCHING HYPOTHESIS IS THAT FSS-SLE WILL BE FEASIBLE FOR AND USABLE BY BOTH FRAIL AND PRE-FRAIL OLDER ADULTS WITH SLE. THE SPECIFIC PROJECT AIMS ARE TO: AIM 1: ADAPT FSS FOR FRAIL AND PRE-FRAIL ADULTS ≥50 YEARS OF AGE WITH SLE. SEMI-STRUCTURED INTERVIEWS WILL BE CONDUCTED WITH RHEUMATOLOGISTS AND PHYSICAL THERAPISTS, AS WELL AS FRAIL AND PRE-FRAIL AGING ADULTS WITH SLE TO GENERATE SUGGESTIONS FOR ADAPTATION OF THE FSS PROGRAM AND TO INCORPORATE KEY STAKEHOLDER PERSPECTIVES IN THE REFINEMENT PROCESS. AIM 2: CONDUCT HEURISTIC AND USABILITY ANALYSES OF THE ADAPTED FSS-SLE PROTOTYPE, ESSENTIAL COMPONENTS OF THE USER-CENTERED DESIGN PROCESS, TO IDENTIFY ANY UPFRONT FUNCTIONAL PROBLEMS (E.G., SYSTEM GLITCHES) WITH FSS- SLE PRIOR TO CONDUCTING A PILOT RANDOMIZED CONTROLLED TRIAL (RCT). THE HEURISTIC ANALYSIS WILL BE BASED ON EXISTING EXERCISE GUIDELINES FOR FRAIL OLDER ADULTS AND DESIGN GUIDELINES FOR AGING ADULTS. THE USABILITY ANALYSIS WILL INCLUDE FRAIL AND PRE-FRAIL ADULTS ≥50 YEARS OF AGE WITH SLE. AIM 3: CONDUCT A PILOT DOUBLE BLIND RCT TO ASSESS FEASIBILITY, USABILITY, ACCEPTABILITY, AND PRELIMINARY EFFICACY OF FSS-SLE IN FRAIL AND PRE-FRAIL ADULTS ≥50 YEARS OF AGE WITH SLE. PARTICIPANTS WILL BE RANDOMIZED TO THE INTERVENTION OR A PA EDUCATIONAL CONTROL ARM. FEASIBILITY WILL BE EVALUATED BY RECRUITMENT AND RETENTION BASED ON FINDINGS FROM FSS. USABILITY AND ACCEPTABILITY WILL BE ASSESSED THROUGH SEMI-STRUCTURED INTERVIEWS AND VALIDATED INSTRUMENTS. PRELIMINARY EFFICACY WILL BE EXAMINED THROUGH CHANGE IN EXERCISE SELF-EFFICACY, A CRITICAL MEDIATOR OF PA BEHAVIOR, FROM BASELINE TO 6, 12, AND 24 WEEKS. THIS PROJECT WILL GENERATE PRELIMINARY DATA TO SUPPORT A MULTICENTER RCT OF FSS-SLE TARGETING FRAIL AND PRE-FRAIL OLDER ADULTS WITH SLE TO IMPROVE DISABILITY AND HEALTH-RELATED QUALITY OF LIFE IN THIS EXPANDING TARGET POPULATION.

187920.00

0.00

0.00

2024-07-23

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Department of Health and Human Services

NEGATIVE REGULATION OF OSTEOCLASTOGENESIS - MANY PATHOLOGICAL CONDITIONS ASSOCIATED WITH EXCESSIVE BONE LOSS ARE CHARACTERIZED BY INCREASED GENERATION OF OSTEOCLASTS, MYELOID LINEAGE CELLS THAT RESORB BONE. THE LONG TERM GOALS OF THIS PROJECT ARE TO ELUCIDATE MOLECULAR PATHWAYS AND MECHANISMS THAT REGULATE MYELOID CELL FUNCTION AND OSTEOCLASTOGENESIS UNDER PATHOLOGICAL INFLAMMATORY CONDITIONS, WITH THE ASSOCIATED GOAL OF USING THIS INFORMATION TO DEVELOP NEW THERAPEUTIC APPROACHES TO SUPPRESS PATHOLOGICAL BONE RESORPTION. INFLAMMATION IS AN IMPORTANT DRIVER OF PATHOLOGICAL BONE LOSS IN DISEASES SUCH AS RHEUMATOID ARTHRITIS AND INFECTIONS. PATHOLOGICAL INFLAMMATION-ASSOCIATED BONE LOSS IS RESISTANT TO STANDARD ANTI-RESORPTIVE THERAPIES; THUS, DEVELOPMENT OF NEW TREATMENTS REPRESENTS AN IMPORTANT UNMET MEDICAL NEED. IN THE PREVIOUS CYCLE OF THIS APPLICATION, WE DEFINED EPIGENETIC AND METABOLIC MECHANISMS BY WHICH INFLAMMATORY CYTOKINES, INTERFERON- (IFN-) AND HYPOXIA REGULATE OSTEOCLASTOGENESIS. WE TESTED THE PATHOPHYSIOLOGICAL IMPORTANCE OF THESE MECHANISMS IN MODELS OF INFLAMMATORY BONE LOSS INCLUDING ARTHRITIS, IMPLANT LOOSENING, SUPRACALVAREAL OSTEOLYSIS, AND ORTHOPEDIC PERIPROSTHETIC JOINT INFECTION (PJI). PJI IS A DEVASTATING COMPLICATION OF JOINT REPLACEMENT SURGERY THAT IS RESISTANT TO TREATMENT AND A MAJOR CAUSE OF MORBIDITY, AND EVEN MORTALITY, IN ORTHOPEDICS. ONE ASPECT OF PJI IS BIOFILM-ASSOCIATED INFECTION AT THE BONE- IMPLANT INTERFACE WHICH RESULTS IN BOSS LOSS AND IMPLANT LOOSENING. USING A CLINICALLY RELEVANT TIBIAL IMPLANT MODEL OF PERSISTENT BIOFILM-ASSOCIATED STAPHYLOCOCCUS AUREUS PJI, WE OBSERVED BONE LOSS AND FAILURE OF OSSEOINTEGRATION. THIS WAS ASSOCIATED WITH SUSTAINED INFLAMMATION AT SITES OF INFECTION, BUT ADAPTIVE IMMUNE T CELLS WERE SUPPRESSED. ADVANCING THE LITERATURE DEMONSTRATING MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS) THAT SUPPRESS T CELLS IN S. AUREUS INFECTIONS, WE NEWLY IDENTIFIED EXPRESSION OF INHIBITORY GENES IN THE SETTING OF A STRONG IFN- SIGNATURE, AN OSTEOCLASTOGENIC PROGRAM SELECTIVELY AT THE BONE-IMPLANT INTERFACE, AND ALTERED MYELOPOIESIS IN THE DISTAL BONE MARROW. INHIBITORY GENE EXPRESSION WAS MARKEDLY HIGHER IN TISSUE ADJACENT TO THE IMPLANT AND BIOFILM, RELATIVE TO SOFT TISSUES INFECTED WITH PLANKTONIC PHASE S. AUREUS. BASED ON THESE RESULTS, OUR OVERARCHING HYPOTHESIS IS THAT S. AUREUS PJI INFECTION INDUCES SUSTAINED INFLAMMATION THAT DRIVES OSTEOCLASTOGENESIS, BUT CONCOMITANTLY INDUCES FEEDBACK INHIBITORY MECHANISMS THAT SUPPRESS ADAPTIVE IMMUNITY AND ATTENUATE CLEARANCE OF INFECTION, RESULTING IN SUBSTANTIAL MORBIDITY. WE PROPOSE THAT GREATER UNDERSTANDING OF THE INFLAMMATORY AND BONE MARROW RESPONSES THAT DRIVE OSTEOCLASTOGENESIS, AND OF FEEDBACK MECHANISMS THAT SUPPRESS THE ADAPTIVE IMMUNE RESPONSE TO PJI, WILL PROVIDE KNOWLEDGE THAT CAN BE USED TO DEVELOP NEW APPROACHES TO SUPPRESS PATHOLOGIC BONE RESORPTION AND TO DEVELOP ADJUVANT IMMUNOTHERAPIES TO HELP CLEAR THIS DEVASTATING CONDITION.

599693.00

0.00

0.00

2025-03-24

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Department of Health and Human Services

ACTIVATION OF SYNOVIAL LINING FIBROBLASTS IN RHEUMATOID ARTHRITIS - PROJECT SUMMARY / ABSTRACT THIS PROPOSAL COMPRISES A FIVE-YEAR RESEARCH AND CAREER DEVELOPMENT PROGRAM FOR MELANIE H. SMITH, MD, PHD TO ACHIEVE INDEPENDENCE AS AN INVESTIGATOR AT THE INTERSECTION OF IMMUNOLOGY AND STROMAL BIOLOGY IN THE HUMAN SYNOVIUM. DR. SMITH IS AN ASSISTANT ATTENDING PHYSICIAN IN THE DIVISION OF RHEUMATOLOGY AT HOSPITAL FOR SPECIAL SURGERY (HSS) AND AN ASSISTANT ATTENDING PROFESSOR OF MEDICINE AT WEILL CORNELL MEDICAL COLLEGE IN NEW YORK CITY. SHE WILL CONDUCT RESEARCH UNDER THE JOINT MENTORSHIP OF DR. LAURA DONLIN (HSS) AND DR. ALEXANDER RUDENSKY (MEMORIAL SLOAN KETTERING CANCER CENTER) FOCUSED ON UNDERSTANDING THE ROLE OF SYNOVIAL FIBROBLASTS IN RHEUMATOID ARTHRITIS (RA). DR. SMITH WILL ENGAGE IN CAREER DEVELOPMENT ACTIVITIES INCLUDING DIDACTICS, WORKSHOPS IN GRANT WRITING AND LEADERSHIP, CONFERENCES, AND ACQUISITION OF TECHNICAL SKILLS AND SCIENTIFIC EXPERTISE. THESE ACTIVITIES WILL BE AUGMENTED THROUGH REGULAR INPUT FROM HER SCIENTIFIC ADVISORY TEAM. THIS TRAINING GRANT WILL GENERATE KEY SKILLS, DATA, AND PUBLICATIONS NECESSARY TO BECOME AN R01-FUNDED INDEPENDENT INVESTIGATOR. SYNOVIAL FIBROBLASTS (FLS) ARE THE MOST ABUNDANT RESIDENT CELLS IN THE SYNOVIUM AND ARE IMPLICATED IN MULTIPLE ASPECTS OF RA PATHOGENESIS. FLS SPECIFICALLY WITHIN THE SYNOVIAL LINING LAYER EXHIBIT EVIDENCE OF EXTENSIVE ACTIVATION AND ARE SELECTIVELY DEFINED BY ACCESSIBILITY OF AP-1 TRANSCRIPTION FACTOR MOTIFS. HERE WE WILL TEST THE CONTRIBUTIONS OF TOLL LIKE RECEPTOR (TLR) LIGANDS FROM THE SYNOVIAL FLUID, AND LOCAL EXPRESSION OF EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) LIGANDS IN ACTIVATING AP-1 IN FLS. THE CENTRAL HYPOTHESIS IS THAT THESE ACTIVATORS OF AP- 1, WHICH ARE PRESENT IN THE SYNOVIAL LINING MICROENVIRONMENT, PRIME LINING FLS TO MOUNT HEIGHTENED RESPONSES TO CYTOKINES DERIVED FROM INFILTRATING LEUKOCYTES, AND THAT AP-1 DRIVEN GENE EXPRESSION DRIVES FLS FUNCTIONAL SPECIALIZATION. WE WILL USE PRIMARY HUMAN SYNOVIAL FIBROBLASTS BOTH IN CULTURE AND DIRECTLY ISOLATED FROM SYNOVIAL TISSUE ALONG WITH SELECTIVE AGONISTS, TARGETED INHIBITORS AND CRISPR INTERFERENCE TO INTERROGATE THE MECHANISTIC BASIS AND FUNCTIONAL CONSEQUENCES OF THE FLS ACTIVATION OBSERVED SPECIFICALLY IN LINING FLS. THE SIGNIFICANCE OF THIS PROPOSAL LIES IN THE IDENTIFICATION OF KEY FACTORS RESPONSIBLE FOR FLS ACTIVATION THAT MAY FURTHER THE DEVELOPMENT OF FLS-TARGETED THERAPIES IN RA. THIS PROPOSAL IS INNOVATIVE IN THE INVESTIGATION OF NON-CYTOKINE DRIVEN PRIMING IN THE ESTABLISHMENT OF INFLAMMATORY MEMORY AND THE IDENTIFICATION OF THE SPECIFIC TRANSCRIPTION FACTORS INVOLVED USING ADVANCED SEQUENCING METHODS AS WELL AS CRISPR IN PRIMARY HUMAN FLS. LONG-TERM, DR. SMITH AIMS TO APPLY THE EXPERTISE GAINED IN THIS PROPOSAL TO IDENTIFY ENVIRONMENTAL AND INFLAMMATORY SIGNALS THAT MAINTAIN AND REGULATE SYNOVIAL INFLAMMATION TO IMPROVE TREATMENT OF RA.

351920.00

0.00

0.00

2024-08-29

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Department of Health and Human Services

ORIGINS AND FUNCTIONS OF INTRAMUSCULAR MACROPHAGES IN DUCHENNE MUSCULAR DYSTROPHY - PROJECT SUMMARY DUCHENNE MUSCULAR DYSTROPHY (DMD), THE MOST COMMON GENETIC MUSCLE DISEASE, IS LETHAL WITH NO CURE AT THIS POINT. MUSCLE PATHOLOGY OF DMD AND ITS MOUSE MODEL MDX5CV FEATURES CHRONIC INFLAMMATION WITH PREDOMINANT MACROPHAGE (MP) INFILTRATION. PRECLINICAL STUDIES BY OUR LAB AND OTHERS DEMONSTRATE THAT AMELIORATING MUSCLE INFLAMMATION IMPROVES MUSCULAR DYSTROPHY PHENOTYPE. IT ALSO IMPROVES LOCAL TISSUE ENVIRONMENT TO PROMOTE MUSCLE REGENERATION AND GENE AND CELL ENGRAFTMENT. TISSUE MACROPHAGES ARE FUNCTIONALLY HETEROGENEOUS WITH DIVERSE ORIGINS. THEY CAN BE PRO-INFLAMMATORY, PRO-FIBROTIC, OR PRO-REGENERATIVE DEPENDING ON THE TISSUE ENVIRONMENT AND ORIGINS. WHILE TISSUE INFLAMMATORY MPS ARE DERIVED FROM BLOOD MONOCYTES (MOS), TISSUE RESIDENT MPS CAN ORIGINATE FROM BLOOD MOS AND/OR EMBRYO. MURINE PERIPHERAL BLOOD MOS CONSIST OF TWO SUBSETS, LY6CHI AND LY6CLO CELLS, WITH CORRESPONDING SUBSETS IN HUMANS. LY6CHI CELLS (CCR2+/CX3CR1LOW) ARE INFLAMMATORY MOS, WHICH ENTER TISSUES IN RESPONSE TO INJURY VIA CC CHEMOKINE RECEPTOR 2 (CCR2) AND THEN DIFFERENTIATE INTO INFLAMMATORY MPS. WITHIN INJURED TISSUES, LY6CHI MPS CAN SWITCH INTO LY6CLO MPS. LY6CHI MOS MAY ALSO CONTRIBUTE TO TISSUE RESIDENT MPS AT THE STEADY STATE. LY6CLO MOS (CCR2-/CX3CR1HI) PATROL THE VASCULAR ENDOTHELIAL SURFACE AND MAY ENTER NORMAL TISSUE VIA CHEMOKINE RECEPTOR CX3CR1 TO REPLENISH RESIDENT MPS. EMBRYO-DERIVED TISSUE RESIDENT MPS ARE ALSO LY6CLO, AND THEY PERSIST INTO ADULT TISSUES THROUGH PROLIFERATIVE SELF-RENEWAL. OUR PRELIMINARY DATA SHOW THAT BOTH LY6CHI AND LY6CLO SUBSETS OF MPS ACCUMULATE IN MDX5CV SKELETAL MUSCLE, AND THAT CCR2 IS ESSENTIAL TO THE MUSCLE RECRUITMENT OF LY6CHI INFLAMMATORY MOS. KNOCKOUT OF CCR2 DIMINISHES INTRAMUSCULAR LY6CHI MPS AT ALL STAGES, BUT IT ONLY REDUCES LY6CLO MPS AT EARLY STAGES. THE REDUCTION OF INTRAMUSCULAR MPS AT THE EARLY STAGES IS ACCOMPANIED BY DECREASED MUSCLE DAMAGE, REDUCED MUSCLE FIBROSIS, AND IMPROVED MUSCLE FUNCTION, WHICH SUPPORTS A PATHOGENIC ROLE FOR THE INTRAMUSCULAR LY6CHI MPS. HOWEVER, THE BENEFICIAL EFFECTS ARE LOST AT THE LATE STAGE IN THE MDX5CV/CCR2-/- MICE AFTER THE EXPANSION OF INTRAMUSCULAR LY6CLO MPS. TARGETING LY6CHI MP ALONE DOES NOT PROVIDE SUSTAINED BENEFITS. WE THUS GENERATE OUR CENTRAL HYPOTHESIS THAT LY6CLO MPS ALSO PLAY A PATHOGENIC ROLE IN THE MDX5CV DIAPHRAGM DYSTROPHY, LY6CLO MPS FROM DIFFERENT ORIGINS MAY CONTRIBUTE DIFFERENTLY, AND TARGETING THE MONOCYTIC ORIGINS IS THERAPEUTICALLY USEFUL. WE WILL TEST OUR HYPOTHESIS BY THREE SPECIFIC AIMS. AIM 1 WILL STUDY THE ORIGINS OF SKELETAL MUSCLE RESIDENT MPS AT THE NORMAL STEADY STATE. AIM 2 WILL DEFINE THE ORIGINS OF INTRAMUSCULAR MPS IN THE MDX5CV DIAPHRAGM. AIM 3 WILL DETERMINE THE EFFECTOR AND REGULATORY FUNCTIONS OF INTRAMUSCULAR MPS DERIVED FROM DIFFERENT ORIGINS IN THE MDX5CV DIAPHRAGM, AND TEST THE THERAPEUTIC POTENTIAL OF TARGETING MONOCYTIC ORIGINS. THIS PROJECT WILL ADDRESS THE KEY QUESTIONS RELATED TO THE INTRAMUSCULAR MPS, AND THE KNOWLEDGE GAINED WILL BE CRITICAL TO THE FUTURE DEVELOPMENT OF NOVEL MONOCYTE/MACROPHAGE-BASED THERAPIES FOR DMD.

1837917.00

0.00

0.00

13-6714749

% TODD GORLEWSKI

Government Instrumentality, Title-Holding Corporation, Charitable Organization, Agricultural Organization, Board of Trade, Pleasure, Recreational, or Social Club, Fraternal Beneficiary Society, Order or Association, Voluntary Employees' Beneficiary Association (Non-Govt. Emps.), Domestic Fraternal Societies and Associations, Teachers Retirement Fund Assoc., Benevolent Life Insurance Assoc., Burial Association, Credit Union, Mutual Insurance Company or Assoc. Other Than Life or Marine, Corp. Financing Crop Operations, Supplemental Unemployment Compensation Trust or Plan, Employee Funded Pension Trust (Created Before 6/25/59), Post or Organization of War Veterans, Legal Service Organization, Black Lung Trust, Multiemployer Pension Plan, Veterans Assoc. Formed Prior to 1880, Trust Described in Sect. 4049 of ERISA, Title Holding Co. for Pensions, etc., State-Sponsored High Risk Health Insurance Organizations, State-Sponsored Workers' Compensation Reinsurance, ACA 1322 Qualified Nonprofit Health Insurance Issuers, Apostolic and Religious Org. (501(d)), Cooperative Hospital Service Organization (501(e)), Cooperative Service Organization of Operating Educational Organization (501(f)), Child Care Organization (501(k)), Charitable Risk Pool, Qualified State-Sponsored Tuition Program, 4947(a)(1) - Private Foundation (Form 990PF Filer)

1987-06

Type of organization and use of contribution: A public charity. Deductibility Limitation: 50% (60% for cash contributions)