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

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

项目成果

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Patrick Robert Griffin其他文献

Patrick Robert Griffin的其他文献

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{{ truncateString('Patrick Robert Griffin', 18)}}的其他基金

Quantifying and modeling ligand-dependent control of RORγ dynamics via structural proteomics
通过结构蛋白质组学对 RORγ 动力学的配体依赖性控制进行量化和建模
  • 批准号:
    10503840
  • 财政年份:
    2022
  • 资助金额:
    $ 2.64万
  • 项目类别:
Quantifying and modeling ligand-dependent control of RORγ dynamics via structural proteomics
通过结构蛋白质组学对 RORγ 动力学的配体依赖性控制进行量化和建模
  • 批准号:
    10704173
  • 财政年份:
    2022
  • 资助金额:
    $ 2.64万
  • 项目类别:
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
  • 批准号:
    10317378
  • 财政年份:
    2021
  • 资助金额:
    $ 2.64万
  • 项目类别:
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
  • 批准号:
    10634739
  • 财政年份:
    2021
  • 资助金额:
    $ 2.64万
  • 项目类别:
Developing nonmuscle II inhibitors for substance use relapse
开发非肌肉 II 抑制剂治疗药物滥用复发
  • 批准号:
    9926588
  • 财政年份:
    2019
  • 资助金额:
    $ 2.64万
  • 项目类别:
Small molecules targeting hepatic glucose production and insulin resistance
针对肝葡萄糖生成和胰岛素抵抗的小分子
  • 批准号:
    9899246
  • 财政年份:
    2019
  • 资助金额:
    $ 2.64万
  • 项目类别:
Small molecules targeting hepatic glucose production and insulin resistance
针对肝葡萄糖生成和胰岛素抵抗的小分子
  • 批准号:
    10357876
  • 财政年份:
    2019
  • 资助金额:
    $ 2.64万
  • 项目类别:
Small molecules targeting hepatic glucose production and insulin resistance
针对肝葡萄糖生成和胰岛素抵抗的小分子
  • 批准号:
    10115706
  • 财政年份:
    2019
  • 资助金额:
    $ 2.64万
  • 项目类别:
Small molecules targeting hepatic glucose production and insulin resistance
针对肝葡萄糖生成和胰岛素抵抗的小分子
  • 批准号:
    10581523
  • 财政年份:
    2019
  • 资助金额:
    $ 2.64万
  • 项目类别:
ALDH1a1 Inhibition As A Therapeutic Target In Visceral Adiposity and Type 2 Diabetes
抑制 ALDH1a1 作为内脏肥胖和 2 型糖尿病的治疗靶点
  • 批准号:
    10197108
  • 财政年份:
    2017
  • 资助金额:
    $ 2.64万
  • 项目类别:

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