R01AG070079

Role of Developmental Signaling Pathways in Maintenance of Spinal Discs - Project Summary/Abstract

Aging is a significant risk factor for the onset of several degenerative diseases, including spinal or intervertebral disc (IVD) degeneration and associated chronic back pain. IVD degeneration and chronic back pain are top neurological disorders and substantial financial burdens, but with no therapy or cure.

Each IVD has a central core of nucleus pulposus (NP), surrounded by orthogonal layers of annulus fibrosus (AF), together sandwiched between a pair of endplates that connect the IVD to the vertebral bodies. Much remains to be learned about the critical regulators of IVD growth, maturation, and maintenance, and whether their loss with age results in IVD pathologies.

We will use conditional genetic mouse models, lineage tracing, heterochronic IVD organ culture, analysis of human disc samples, and unbiased approaches of high throughput transcriptomics to identify crucial developmental regulators, including Sonic Hedgehog (SHH), in IVD maintenance to fill in these gaps.

Our central hypothesis is that SHH expression by the NP cells is essential for growth and maturation of the IVD, and its age-related loss leads to IVD pathologies. The expression of SHH signaling ligand by the notochord is crucial for embryogenesis. Previously, we showed that postnatal NP cells continue to express SHH, and SHH signaling regulates NP cell proliferation and ECM production by NP and AF. Though all NP cells are descendants of SHH-expressing notochord cells, our preliminary data reveals that most of them turn off SHH expression after birth. Besides, age-related decline in SHH expression is associated with terminal differentiation of NP cells into multinucleated syncytium and subsequent loss along with the declined expression of ECM proteins that are important for IVD function.

Our preliminary data also show that conditional targeting of SHH in adult mice accelerates IVD aging, along with the loss of NP cells, providing the logical premise for this new project. These data indicate that SHH signaling is crucial; however, we do not know its precise function during growth and maturation and whether it is critical for aging IVDs.

Aim 1 will test the hypothesis that SHH is a critical signaling pathway and its downstream regulators play a distinct role during infancy and maturation, and its loss causes IVD pathologies. Aim 2 will test the hypothesis that SHH-expressing NP cells are the progenitor cells, and the stochastic expression of SHH regulates all NP cells' molecular heterogeneity. Aim 3 will investigate the beneficial effects of SHH signaling for delaying aging.

We expect that the completion of this study will provide insights into the role of SHH as a critical regulator of growth and maturation of the IVD and identify avenues for targeting such molecules to reverse or delay the aging process and improve the quality of life of the aging population.

The Hospital For Special Surgery Fund

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM; 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. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH 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.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

New York, New York 100214823 United States

Single Zip Code

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 04/30/27 and the total obligations have increased 383% from $687,251 to $3,322,079.