IGFBP-5 and Hsp70 in Extracellular Matrix Homeostasis and Fibrosis

IGFBP-5 和 Hsp70 在细胞外基质稳态和纤维化中的作用

基本信息

项目摘要

DESCRIPTION (provided by applicant): Interstitial lung disease (ILD) comprises a group of more than 130 disorders characterized by scarring, or fibrosis, of the lungs. The causes of some of the ILDs are known, including those associated with connective tissue diseases such as systemic sclerosis (SSc, or scleroderma). Despite intense study, however, the basic mechanisms responsible for the initiation and perpetuation of fibrosis remain elusive. This proposal outlines a detailed 5-year scientific and career development plan designed to facilitate the applicant's successful transition to the role of independent investigator and provide a solid foundation for her to become a world-class researcher in matrix biology and fibrotic lung disease. Work performed in the mentor's laboratory has demonstrated increased expression of insulin-like growth factor binding protein 5 (IGFBP-5) in scleroderma fibroblasts and fibrotic lung tissue from patients with idiopathic pulmonary fibrosis. Furthermore, over-expression of IGFBP-5 in vitro and in vivo results in aberrant extracellular matrix (ECM) production, a hallmark of fibrotic disease. IGFBP-5 induces expression of the major extracellular matrix proteins fibronectin and collagen I. Additionally, there is reduced expression of the Hsp70 heat shock protein both in vivo in lung tissue and primary fibroblasts from patients with SSc-associated pulmonary fibrosis and in vitro in response to lGFBP-5 over-expression. We hypothesize that IGFBP-5 increases production of matrix structural proteins through Hsp70-dependent pathways, thereby disrupting ECM homeostasis and resulting in fibrosis. The specific aims of this proposal are to (1) identify the mechanism of lGFBP-5 mediated ECM imbalance, (2) characterize the regulation of Hsp70 by IGFBP-5, and (3) characterize the role of Hsp70 and the heat shock transcription factors in the regulation of ECM deposition. Biochemical and genetic in vitro studies in primary mouse and human lung fibroblasts will elucidate signaling pathways and transcription factors involved in lGFBP-5's regulation of Hsp70 and the ECM, as well as in regulation of ECM production by heat shock proteins and transcription factors. Complementary in vivo work will be conducted in a mouse model of IGFBP-5 over-expression in the lung. In total, these studies will provide mechanistic insight into the IGFBP-5 pro-fibrotic cascade and the role of the heat shock response in ECM deposition, leading to an enhanced understanding of the derangements in extracellular matrix homeostasis that lead to fibrosis. RELEVANCE (See instructions): The interstitial lung diseases (ILDs) result in significant morbidity and mortality, and there are no effective medical therapies to reverse fibrosis. The proposed investigations will not only serve to define how lGFBP-5 and Hsp70 affect extracellular matrix balance, but will also provide better insight into the mechanisms of fibroproliferative diseases in the lung and serve as a foundation for the development of novel diagnostic and therapeutic strategies for the ILDs. (End of Abstract)
描述(由申请人提供):间质性肺病(ILD)包括一组超过130种以肺部瘢痕或纤维化为特征的疾病。一些ild的病因是已知的,包括与结缔组织疾病如系统性硬化症(SSc,或硬皮病)相关的ild。然而,尽管进行了大量的研究,但纤维化发生和持续的基本机制仍然难以捉摸。本提案概述了详细的5年科学和职业发展计划,旨在促进申请人成功过渡到独立研究者的角色,并为其成为世界一流的基质生物学和纤维化肺疾病研究人员提供坚实的基础。在导师的实验室进行的工作表明,胰岛素样生长因子结合蛋白5 (IGFBP-5)在硬皮病成纤维细胞和特发性肺纤维化患者的纤维化肺组织中的表达增加。此外,体外和体内IGFBP-5的过度表达导致细胞外基质(ECM)产生异常,这是纤维化疾病的一个标志。IGFBP-5诱导主要的细胞外基质蛋白纤维连接蛋白和胶原蛋白i的表达。此外,在体内,在ssc相关性肺纤维化患者的肺组织和原代成纤维细胞中,以及在体外,由于lGFBP-5的过度表达,Hsp70热休克蛋白的表达都有所降低。我们假设IGFBP-5通过hsp70依赖途径增加基质结构蛋白的产生,从而破坏ECM稳态并导致纤维化。本课题的具体目的是:(1)明确lGFBP-5介导ECM失衡的机制;(2)表征IGFBP-5对Hsp70的调控;(3)表征Hsp70及热休克转录因子在ECM沉积调控中的作用。在原代小鼠和人肺成纤维细胞的体外生化和遗传学研究将阐明lGFBP-5调控Hsp70和ECM的信号通路和转录因子,以及热休克蛋白和转录因子对ECM产生的调控。补充的体内工作将在肺IGFBP-5过表达的小鼠模型中进行。总的来说,这些研究将为IGFBP-5促纤维化级联机制和热休克反应在ECM沉积中的作用提供深入的见解,从而增强对导致纤维化的细胞外基质稳态紊乱的理解。相关性(见说明):间质性肺疾病(ILDs)导致显著的发病率和死亡率,并且没有有效的药物治疗来逆转纤维化。这项研究不仅将有助于确定lGFBP-5和Hsp70如何影响细胞外基质平衡,还将更好地了解肺部纤维增生性疾病的机制,并为开发新的ILDs诊断和治疗策略奠定基础。(摘要结束)

项目成果

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Kristen L Veraldi其他文献

Kristen L Veraldi的其他文献

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{{ truncateString('Kristen L Veraldi', 18)}}的其他基金

IGFBP-5 and Hsp70 in Extracellular Matrix Homeostasis and Fibrosis
IGFBP-5 和 Hsp70 在细胞外基质稳态和纤维化中的作用
  • 批准号:
    7893829
  • 财政年份:
    2009
  • 资助金额:
    $ 12.49万
  • 项目类别:
IGFBP-5 and Hsp70 in Extracellular Matrix Homeostasis and Fibrosis
IGFBP-5 和 Hsp70 在细胞外基质稳态和纤维化中的作用
  • 批准号:
    8098829
  • 财政年份:
    2009
  • 资助金额:
    $ 12.49万
  • 项目类别:
IGFBP-5 and Hsp70 in Extracellular Matrix Homeostasis and Fibrosis
IGFBP-5 和 Hsp70 在细胞外基质稳态和纤维化中的作用
  • 批准号:
    8279298
  • 财政年份:
    2009
  • 资助金额:
    $ 12.49万
  • 项目类别:
IGFBP-5 and Hsp70 in Extracellular Matrix Homeostasis and Fibrosis
IGFBP-5 和 Hsp70 在细胞外基质稳态和纤维化中的作用
  • 批准号:
    7740455
  • 财政年份:
    2009
  • 资助金额:
    $ 12.49万
  • 项目类别:

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