R01AR077145

Role of SHH/Brachyury Axis in the Maintenance of the Postnatal Intervertebral Disc - Project Summary/Abstract

The goal of this proposal is to identify the role of critical developmental molecules in the growth and maintenance of the postnatal intervertebral disc (IVD, or disc), and how the loss of these molecules with age results in pathological changes in the disc. The disc is a cartilaginous structure present between each vertebra. It consists of three components: the notochord-derived central nucleus pulposus (NP), surrounded by orthogonal layers of annulus fibrosus (AF), and endplate (EP) adjacent to the growth plate.

With age or injury, the disc undergoes degenerative changes leading to chronic lower back pain (CLBP), which affects almost 80% of the adult US population. Much remains to be learned about the cellular and molecular basis of disc growth differentiation and aging, which has limited the development of effective therapies.

We will use conditional genetic mouse models, lineage-tracing, and disc injury models to identify the function(s) of a crucial developmental regulator, Brachyury (BRA), in the disc. Our central hypothesis is that BRA expression by the NP cells is essential for disc growth and maintenance, and its loss during aging leads to the pathological changes in the disc. BRA is a T-box transcription factor and a notochordal marker. Previously, we showed that postnatal NP cells express BRA, but its expression decreases with age. We also found that Sonic Hedgehog (SHH), an important notochord signal secreted by NP cells, regulates postnatal disc growth and differentiation, and regulates BRA expression.

While the total number of NP cells decreased with age, the BRA-expressing NP cells also decreased with age and were replaced by non-BRA-expressing "chondrocyte-like cells" (CLCs). The lineage relationship between CLCs and the BRA-expressing cells they replace is unknown, nor is it known how (or if) the loss of BRA expression leads to disc aging. Our preliminary data showed that all NP cells are lost in an aged mouse disc. We also showed that conditional targeting of SHH in adult mice accelerates disc aging, along with the loss of BRA expression. We further showed that haploinsufficiency of BRA accelerates disc aging, providing the logical premise for this new project.

Aim 1 tests the hypothesis that BRA is a primary transcriptional regulator downstream of SHH signaling and regulates growth and maintenance of postnatal disc. Aim 2 will test the hypothesis that NP cells diverge into two molecularly heterogeneous populations, which differ with respect to SHH and BRA expression. Aim 3 will test the hypothesis that BRA controls the survival of NP cells and prevents them from differentiating into "chondrocyte-like" cells.

We expect that the findings from this study will provide insights into the role of developmental molecules in the maintenance of the postnatal disc during growth and aging. Additionally, it will identify avenues for targeting such molecules to reverse the aging process, aiding the development of therapeutics for the treatment of disc-related disorders and lower back pain (LBP).

The Hospital For Special Surgery Fund

THE NATIONAL INSTITUTE OF 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 BODY'S 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]

New York, New York 100214823 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 432% from $565,136 to $3,008,731.