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PPARG regulates osteocyte bioenergetics and function during aging

PPARG 在衰老过程中调节骨细胞生物能和功能

基本信息

批准号：
10426408
负责人：
Patrick Robert Griffin
金额：
$ 2.64万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2021-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10426408
关键词：
Adipocytes Affect Age-Related Bone Loss Aging Agonist American Applications Grants Bioenergetics Bone Resorption Bone remodeling C57BL/6 Mouse CRISPR/Cas technology Cell physiology Cells Chronic Disease Coculture Techniques Diabetes Mellitus Diagnosis Disease Elderly Endocrine Energy Metabolism Enhancers Exhibits Fracture Genetic Genetic Transcription Homeostasis Hormonal Hyperglycemia Impairment In Vitro Knowledge Lead Maintenance Metabolic Diseases Metabolic dysfunction Metabolism Minerals Mitochondria Molecular Mus Nuclear Receptors Organ Organ Culture Techniques Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteoporosis PPAR gamma Pathway interactions Pharmacology Population Process Production Proteins Proteomics Quality of life Regulation Research Role Signal Transduction Skeleton TNFSF11 gene Testing aged aging population bone bone cell bone loss bone mass bone metabolism bone quality effective therapy experimental study improved in vivo Model inhibitor/antagonist insight mouse model novel osteoblast differentiation paracrine preference programs promoter protein complex response rosiglitazone skeletal transcriptomics

项目摘要

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 which bioenergetic program is largely unknown. New evidence indicates that nuclear receptor PPARG, which is a global regulator of energy metabolism and 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 an insight into the connection between osteocyte bioenergetics, its function in bone metabolism and systemic energy metabolism, and whether bone acts as the body “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 γOTKO mice, bone organ cultures, and osteocyte-like MLO-Y4 cells with down-regulated PPARG, in combination with transcriptomics, quantitative proteomics, and coculture experiments, PPARG 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 dynamics of PPARG interactome on PPRE sequences present in 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 elderly.

随着年龄的增长，骨质流失和能量代谢障碍通常会导致骨折和糖尿病。作为一个