R01AR079863

TARGETING JMJD3 MITIGATES HETEROTOPIC OSSIFICATION - PROJECT SUMMARY/ABSTRACT

HETEROTOPIC OSSIFICATION (HO) IS THE PATHOLOGIC FORMATION OF EXTRA-SKELETAL THAT IS ALWAYS PRECEDED BY AN INFLAMMATORY INSULT AND OCCURS IN ~20% OF PATIENTS AFTER HIP ARTHROPLASTY, BURNS OR MUSCULOSKELETAL INJURY.

CURRENTLY, NO THERAPEUTICS OR PHYSICAL THERAPY-BASED PROTOCOLS EXIST TO PREVENT OR TREAT HO.

IN THIS REGARD, THERE IS A VOID IN OUR UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING HO FORMATION AND PROGRESSION.

WE PRESENT DATA THAT THE HISTONE DEMETHYLASE, JMJD3, IS INCREASED IN HO MACROPHAGES (MFS) RESULTING IN PERSISTENT PRODUCTION OF TRANSFORMING GROWTH FACTOR-BETA (TGF1) AT THE HO INJURY SITE.

THIS EXCESS TGF1 CAUSES ABERRANT MESENCHYMAL PROGENITOR CELL (MPC) OSTEOCHONDRAL OSSIFICATION, RESULTING IN HO FORMATION.

FURTHER, USING HUMAN CELLS AND OUR EXPERIMENTAL CLINICALLY RELEVANT MURINE MODELS OF HO, WE HAVE IDENTIFIED THAT INTERFERON-BETA (IFNSS), VIA A JANUS KINASE (JAK) / SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) MECHANISM INDUCES JMJD3 IN MFS.

THESE RESULTS HAVE LED TO OUR CENTRAL HYPOTHESIS THAT IFN/JAK/STAT3 SIGNALING DIRECTLY INCREASES JMJD3 EXPRESSION IN HO TISSUE MACROPHAGES AND THAT JMDJ3 INCREASES MACROPHAGE TGFB1 EXPRESSION THUS PROMOTING ABERRANT MPC FATE AND HO FORMATION.

WE FURTHER POSTULATE THAT MF SPECIFIC REPRESSION OF JAK1/3 OR JMJD3 AND THUS, TGF1 PRODUCTION USING A NOVEL TARGETED NANOTHERAPY WILL HALT HO FORMATION AND PROGRESSION.

AS SUCH, WE PROPOSE THE FOLLOWING AIMS:

AIM 1: ELUCIDATE THE IFN1/JAK1/STAT3- MEDIATED MECHANISM THAT REGULATES MF-SPECIFIC JMJD3 EXPRESSION IN HUMAN AND MOUSE HO WOUNDS.

AIM 2: DEFINE THE REGULATION OF WOUND MF JMJD3 ON TGF1 EXPRESSION AND THE PARACRINE EFFECTS OF MF JMJD3 ON MPC FATE UNDER CONDITIONS OF NORMAL AND ABERRANT WOUND HEALING (HO) IN VIVO.

AIM 3: EXAMINE THE MF SPECIFICITY AND THERAPEUTIC EFFICACY AND TIMING OF MF-TARGETED JMJD3 AND JAK1/3 NANOPARTICLES ON MPC PHENOTYPE AND HO FORMATION.

IN THIS TRANSLATIONAL PROJECT, OUR DATA WILL PAVE THE WAY FOR THE DEVELOPMENT OF PROMISING PREVENTIVE NANOTHERAPEUTIC AGENTS AIMED AT CELL-SPECIFIC TARGETING OF EPIGENETIC ENZYMES THAT MEDIATE MF REGULATION OF MPC FATE AND THEREBY PREVENT HO DEVELOPMENT FOLLOWING INJURY.

Regents Of The University Of Michigan

THE NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) MISSION IS TO SUPPORT RESEARCH INTO THE CAUSES, TREATMENT, AND PREVENTION OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES; TRAINING OF BASIC AND CLINICAL SCIENTISTS TO CARRY OUT THIS RESEARCH; AND DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN THESE DISEASES. THE EXTRAMURAL PROGRAM PROMOTES AND SUPPORTS BASIC, TRANSLATIONAL, AND CLINICAL STUDIES OF SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES, SKIN BIOLOGY AND DISEASES, BONE BIOLOGY AND DISEASES, MUSCLE BIOLOGY AND DISEASES, AND JOINT BIOLOGY AND DISEASES AND ORTHOPAEDICS. NIAMS SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES PROGRAMS ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS AND OBSERVATIONAL AND MECHANISTIC STUDIES, FOCUSED ON IMMUNE-MEDIATED ARTHRITIS AND AUTOIMMUNE-RELATED ACUTE AND CHRONIC DISORDERS IN ADULTS AND CHILDREN. NIAMS SKIN BIOLOGY AND DISEASES PROGRAMS SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN SKIN, INCLUDING BOTH COMMON AND RARE SKIN DISEASES. THESE PROGRAMS INCLUDE INVESTIGATIONS OF THE BASIC MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY OF SKIN, AS WELL AS STUDIES OF SKIN AS AN IMMUNE, SENSORY, ENDOCRINE, AND METABOLIC ORGAN. NIAMS BONE BIOLOGY AND DISEASES PROGRAMS SUPPORT RESEARCH ON THE CONTROL OF BONE FORMATION, RESORPTION, AND MINERALIZATION AS WELL AS THE EFFECTS OF SIGNALING MOLECULES ON BONE CELLS. THEY SUPPORT CLINICAL STUDIES OF INTERVENTIONS TO PREVENT FRACTURES ASSOCIATED WITH OSTEOPOROSIS AND RESEARCH INTO LESS COMMON BONE DISEASES. NIAMS MUSCLE BIOLOGY AND DISEASES PROGRAMS ENCOURAGE RESEARCH ON MUSCLE DEVELOPMENTAL BIOLOGY, GROWTH, MAINTENANCE, AND HYPERTROPHY; PHYSIOLOGY OF CONTRACTION; STRUCTURAL BIOLOGY OF THE CONTRACTILE APPARATUS; DISEASE MECHANISMS; BIOMARKERS AND OUTCOME MEASURES; AND DEVELOPMENT AND CLINICAL TESTING OF THERAPIES FOR CONDITIONS INCLUDING THE MUSCULAR DYSTROPHIES. NIAMS JOINT BIOLOGY, DISEASES, AND ORTHOPAEDICS PROGRAMS SUPPORT A BROAD SPECTRUM OF RESEARCH CENTERED ON THE INTERPLAY AMONG THE BODYS MUSCLES, BONES, AND CONNECTIVE TISSUES. THEY ENCOURAGE TISSUE ENGINEERING AND REGENERATIVE MEDICINE RESEARCH, MOLECULAR BIOLOGY, IMAGING, AND CLINICAL RESEARCH, AND THE TREATMENT AND PREVENTION OF ORTHOPAEDIC CONDITIONS. NIAMS PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

Ann Arbor, Michigan 481091276 United States

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NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 04/30/26 to 12/31/26 and the total obligations have increased 371% from $643,472 to $3,032,100.