Biomechanical Regulation of Intra-Articular Adipose Tissue Inflammation

关节内脂肪组织炎症的生物力学调节

基本信息

  • 批准号:
    8773923
  • 负责人:
  • 金额:
    $ 8.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-01 至 2017-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Intra-articular adipose tissue is an important structural tissue within joints and is increasingly recognized as a critical mediator of inflammation. The extrinsic factors that regulate intra-articular adipose tissue inflammation are unknown. Identifying such factors and the molecular mechanisms by which they impact joint inflammation will advance the development of new treatments for joint injury and musculoskeletal disability. The applicant's long-term goal is to develop therapies to treat and prevent obesity-associated osteoarthritis by identifying biomechanical and metabolic factors that promote the resolution of joint inflammation. This application focuses on the mechanobiology of inflammatory signaling in intra-articular fat pads. The objective here is to identify the effect of joint loading on the expression of inflammatory adipokines within the infrapatellar fat pad (IFP) and to determine whether adipose tissue macrophages (ATMs) mediate this response. The central hypothesis is that physiologic joint loading due to exercise induces resident ATMs to initiate a pro-fibrotic response that restricts adipocyte hypertrophy and thereby attenuates pro-inflammatory adipokine expression. The hypothesis and focus on ATMs as mechano-sensitive pro-fibrotic mediators in the IFP is based on a comprehensive literature review and preliminary data generated in the applicant's laboratory. These findings indicate that compared to subcutaneous fat, the IFP has an elevated expression of pro-fibrotic growth factors, fibronectin, and cytokines. Preliminary wheel running studies also show that the IFP is a dynamic structural tissue that increases extracellular matrix deposition in response to exercise. Guided by these data, the project will test the hypothesis using two specific aims: 1) Determine the time-course of in vivo and ex vivo biomechanical stimulation on mediators of macrophage infiltration, polarization, and IFP fibrosis; and 2) Determine the requirement of resident ATMs on biomechanically-stimulated IFP fibrosis and adipokine expression. A well- established voluntary wheel running mouse model will be used to evaluate the effect of increased IFP mechanical stimulation on gene, protein, and cellular outcome measures. The applicant's lab will also utilize an ex vivo tissue compression system for conducting compressive loading experiments on rat IFP samples. Under the second aim, resident ATMs will be depleted in these in vivo and ex vivo models with liposomal clodronate to determine if ATMs mediate the effect of biomechanical stimulation on IFP fibrosis and adipokine expression. The proposed research is significant because it is expected that biomechanical stimulation will greatly contribute to the paracrine inflammatory signaling function of intra-articular fat pads. Ultimately, such knowledge is expected to lead to the development of novel therapeutic targets for pre-clinical testing in the prevention or treatment of diseases involving musculoskeletal inflammation and physical disability.
描述(由申请人提供):关节内脂肪组织是关节内的重要结构组织,并且越来越多地被认为是炎症的关键介质。调节关节内脂肪组织炎症的外在因素尚不清楚。识别这些因素及其影响关节炎症的分子机制将促进关节损伤和肌肉骨骼残疾新疗法的开发。申请人的长期目标是通过识别促进关节炎症消退的生物力学和代谢因素,开发治疗和预防肥胖相关骨关节炎的疗法。该应用程序的重点是在关节内脂肪垫炎症信号的机械生物学。本研究的目的是确定关节负荷对髌下脂肪垫(IFP)内炎性脂肪因子表达的影响,并确定脂肪组织巨噬细胞(ATM)是否介导这种反应。中心假设是由于运动引起的生理关节负荷诱导驻留ATM启动限制脂肪细胞肥大的促纤维化反应,从而减弱促炎性脂肪因子表达。关于ATM作为IFP中机械敏感性促纤维化介质的假设和重点是基于全面的文献综述和申请人实验室生成的初步数据。这些发现表明,与皮下脂肪相比,IFP具有促纤维化生长因子、纤连蛋白和细胞因子的升高的表达。 初步的轮跑研究还表明,IFP是一个动态的结构组织,增加细胞外基质沉积响应运动。在这些数据的指导下,该项目将使用两个特定目标来测试假设:1)确定体内和体外生物力学刺激对巨噬细胞浸润、极化和IFP纤维化介质的时间过程; 2)确定常驻ATM对生物力学刺激的IFP纤维化和脂肪因子表达的要求。将使用完善的自主轮跑小鼠模型来评估增加的IFP机械刺激对基因、蛋白质和细胞结果测量的影响。申请人的实验室还将利用离体组织压缩系统对大鼠IFP样本进行压缩载荷实验。在第二个目标下,将在这些体内和离体模型中用脂质体氯膦酸盐耗尽驻留的ATM,以确定ATM是否介导生物力学刺激对IFP纤维化和脂肪因子表达的影响。这项研究意义重大,因为生物力学刺激将极大地促进关节内脂肪垫的旁分泌炎症信号功能。最终,这些知识预计将导致开发新的治疗靶点,用于预防或治疗涉及肌肉骨骼炎症和身体残疾的疾病的临床前测试。

项目成果

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TIMOTHY M GRIFFIN其他文献

TIMOTHY M GRIFFIN的其他文献

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{{ truncateString('TIMOTHY M GRIFFIN', 18)}}的其他基金

Metabolic Phenotyping Core
代谢表型核心
  • 批准号:
    10571892
  • 财政年份:
    2021
  • 资助金额:
    $ 8.55万
  • 项目类别:
Metabolic Phenotyping Core
代谢表型核心
  • 批准号:
    10339349
  • 财政年份:
    2021
  • 资助金额:
    $ 8.55万
  • 项目类别:
Metabolic Phenotyping Core
代谢表型核心
  • 批准号:
    10090978
  • 财政年份:
    2021
  • 资助金额:
    $ 8.55万
  • 项目类别:
CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Optimizing the Host Environment for Intra-articular Osteoarthritis Therapies
CMA:缓解关节炎疼痛的软骨修复策略 (CaRe AP):优化关节内骨关节炎治疗的宿主环境
  • 批准号:
    10376737
  • 财政年份:
    2020
  • 资助金额:
    $ 8.55万
  • 项目类别:
CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Optimizing the Host Environment for Intra-articular Osteoarthritis Therapies
CMA:缓解关节炎疼痛的软骨修复策略 (CaRe AP):优化关节内骨关节炎治疗的宿主环境
  • 批准号:
    9890590
  • 财政年份:
    2020
  • 资助金额:
    $ 8.55万
  • 项目类别:
CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Optimizing the Host Environment for Intra-articular Osteoarthritis Therapies
CMA:缓解关节炎疼痛的软骨修复策略 (CaRe AP):优化关节内骨关节炎治疗的宿主环境
  • 批准号:
    10618788
  • 财政年份:
    2020
  • 资助金额:
    $ 8.55万
  • 项目类别:
Targeting Molecular Transducers of Exercise for Osteoarthritis Therapies
靶向运动分子传感器治疗骨关节炎
  • 批准号:
    10292949
  • 财政年份:
    2019
  • 资助金额:
    $ 8.55万
  • 项目类别:
Targeting Molecular Transducers of Exercise for Osteoarthritis Therapies
靶向运动分子传感器治疗骨关节炎
  • 批准号:
    10516067
  • 财政年份:
    2019
  • 资助金额:
    $ 8.55万
  • 项目类别:
Targeting Molecular Transducers of Exercise for Osteoarthritis Therapies
靶向运动分子传感器治疗骨关节炎
  • 批准号:
    10045511
  • 财政年份:
    2019
  • 资助金额:
    $ 8.55万
  • 项目类别:
Targeting Molecular Transducers of Exercise for Osteoarthritis Therapies
靶向运动分子传感器治疗骨关节炎
  • 批准号:
    9780367
  • 财政年份:
    2019
  • 资助金额:
    $ 8.55万
  • 项目类别:

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成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
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