R01AG071332

PPARG Regulates Osteocyte Bioenergetics and Function During Aging

Bone loss and impairment in energy metabolism with aging prevalently lead to fractures and diabetes. As an organ, the skeleton is one of the largest consumers of energy needed for bone remodeling and maintenance of bone homeostasis.

Bone remodeling is under control of osteocytes, which constitute 90-95% of bone cells, and whose bioenergetic program is largely unknown. New evidence indicates that nuclear receptor PPARG, which is a global regulator of energy metabolism and a pharmacological target to treat hyperglycemia, regulates osteocyte energy metabolism and their function, including production of sclerostin, an inhibitor of Wnt pathway activity and a key protein regulating bone remodeling.

Research proposed in this application will provide insight into the connection between osteocyte bioenergetics, its function in bone metabolism, and systemic energy metabolism, and whether bone acts as the body's "energostat" via osteocyte endocrine activities. The leading hypothesis is that changes in PPARG activity with aging alter osteocyte function and bioenergetics, resulting in simultaneous decrease in bone formation and decrease in energy metabolism. This hypothesis will be tested in three specific aims.

Aim 1 will determine how fuel choice and aging affect osteocyte function and whether these processes are PPARG dependent. With the use of aged C57BL/6 and OTKO mice, bone organ cultures, and osteocyte-like MLO-Y4 cells with down-regulated PPARG, in combination with transcriptomics, quantitative proteomics, and co-culture experiments, PPARG's contribution to osteocyte aging will be defined.

Aim 2 will contrast the PPARG protein interactome of osteocytes with the interactome of adipocytes, in response to either full agonist rosiglitazone or the inverse agonist SR10171, in order to define an optimal PPARG modulator for its beneficial effects on bone and metabolism. The analysis will be done on osteocyte-like MLO-Y4 cells using quantitative tandem mass tag proteomics.

Aim 3 will define the dynamics of the PPARG interactome on PPRE sequences present in the SOST promoter as a function of aging and in response to pharmacological modulation of PPARG activity.

The premise of this application is to set a stage for precise pharmacologic manipulation with PPARG activities in osteocytes to simultaneously improve skeletal and metabolic dysfunction in the elderly.

University Of Toledo

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]

Toledo, Ohio 43614 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 401% from $678,086 to $3,398,240.