Role of Cilp1 in Post-Natal Heart Response to Injury

Cilp1 在产后心脏损伤反应中的作用

基本信息

  • 批准号:
    10580830
  • 负责人:
  • 金额:
    $ 54.47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-06-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

Matricellular proteins are constituents of the extracellular matrix (ECM). They are normally expressed highly during embryonic development but absent/low in adult tissues unless activated by cues for tissue remodeling. Matricellular proteins shape ECM properties through interactions with structural proteins, growth factors, and cell receptors during organ development and differentiation. In an attempt to identify molecular signatures unique to irreversible cardiac fibrosis, we performed proteomics of fibrotic heart and liver and found that cartilage intermediate layer protein 1 (Cilp1) is differentially upregulated in the infarcted heart. Cilp1 is normally associated with bone and cartilage development. Its function and mechanism of action in adult heart diseases are unknown. We generated Cilp1 knockout (KO) mice from commercial Cilp1fl/fl mice and transgenic (Tg) mice with Cilp1 overexpressed in myofibroblasts. While deletion of Cilp1 reduced adverse cardiac remodeling upon myocardial infarction (MI), overexpression of Cilp1 worsened it. Cilp1 is expressed predominantly in cardiac fibroblasts. We hypothesize that fibroblast Cilp1 promotes inflammation and myofibroblast proliferation upon MI injury. We now generated fibroblast conditional fbKO mice (PostnMCM;Cilp1fl/fl and Tcf21MCM;Cilp1fl/fl that contain a tamoxifen inducible Cre-recombinase expression cassette within Periostin (Postn) and Tcf21 genetic locus, respectively). Aim 1. To determine the cell-type specific function of Cilp1 in post-MI cardiac remodeling. We will delete Cilp1 in cardiac fibroblasts before and post-MI day (d) 1 & d4 to investigate its effect on cardiac remodeling, including cardiac function, inflammation, myofibroblast proliferation/differentiation, and collagen remodeling. We will also perform proteomics of myofibroblasts isolated from these mouse hearts. The role of fibroblast Cilp1 in regulation of gene transcription in various heart cell types will be investigated with single-nuclei RNA-seq of infarcted WT and Cilp1 fbKO hearts at post-MI d3. Aim 2. To establish the molecular function of Cilp1 and its mechanism of action. Preliminary studies showed that Cilp1 protein in culture medium promotes myofibroblast proliferation via the mTORC1 pathway and binds scavenge receptor CD36. Cilp1 may interact with cell receptor/growth factor, promoting cell proliferation and inflammatory gene expression via receptor-mediated signaling pathways. To test this hypothesis, we will identify the minimal functional domain(s) of Cilp1 via mutagenesis and potential Cilp1- binding partners using both screen- and candidate-based assays and will establish how Cilp1 may act as a paracrine factor to regulate the cellular phenotypes of various heart cell types via receptor-mediated signaling pathways. We will also measure blood level of Cilp1 in mice before and after an anti-fibrogenic therapy upon MI injury. Matricellular proteins are clinically tractable owing to their accessibility to systemically delivered therapeutic reagents. Our preliminary studies established a pathological role of Cilp1 in post-MI remodeling. This proposal will establish how Cilp1 instructs development and differentiation of heart cells and gene expression to promote adverse remodeling, thus providing mechanistic insight on how to target this protein.
细胞蛋白是细胞外基质(ECM)的组成部分。它们通常高度表达

项目成果

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Zhi-Ping Liu其他文献

Zhi-Ping Liu的其他文献

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{{ truncateString('Zhi-Ping Liu', 18)}}的其他基金

Role of Cilp1 in Post-Natal Heart Response to Injury
Cilp1 在产后心脏损伤反应中的作用
  • 批准号:
    10365053
  • 财政年份:
    2022
  • 资助金额:
    $ 54.47万
  • 项目类别:
Epigenetic Regulation of Cardiac Hypertrophy and Heart Failure
心脏肥大和心力衰竭的表观遗传调控
  • 批准号:
    8511805
  • 财政年份:
    2012
  • 资助金额:
    $ 54.47万
  • 项目类别:
Epigenetic Regulation of Cardiac Hypertrophy and Heart Failure
心脏肥大和心力衰竭的表观遗传调控
  • 批准号:
    8656758
  • 财政年份:
    2012
  • 资助金额:
    $ 54.47万
  • 项目类别:
Epigenetic Regulation of Cardiac Hypertrophy and Heart Failure
心脏肥大和心力衰竭的表观遗传调控
  • 批准号:
    8371213
  • 财政年份:
    2012
  • 资助金额:
    $ 54.47万
  • 项目类别:
Role of FOXO4 in atherosclerosis
FOXO4 在动脉粥样硬化中的作用
  • 批准号:
    7840759
  • 财政年份:
    2009
  • 资助金额:
    $ 54.47万
  • 项目类别:
Role of FOXO4 in atherosclerosis
FOXO4 在动脉粥样硬化中的作用
  • 批准号:
    7269313
  • 财政年份:
    2006
  • 资助金额:
    $ 54.47万
  • 项目类别:
Role of FOXO4 in atherosclerosis
FOXO4 在动脉粥样硬化中的作用
  • 批准号:
    7135207
  • 财政年份:
    2006
  • 资助金额:
    $ 54.47万
  • 项目类别:
Role of FOXO4 in atherosclerosis
FOXO4 在动脉粥样硬化中的作用
  • 批准号:
    7624276
  • 财政年份:
    2006
  • 资助金额:
    $ 54.47万
  • 项目类别:
Role of FOXO4 in atherosclerosis
FOXO4 在动脉粥样硬化中的作用
  • 批准号:
    7421057
  • 财政年份:
    2006
  • 资助金额:
    $ 54.47万
  • 项目类别:
Role of FOXO4 in atherosclerosis
FOXO4 在动脉粥样硬化中的作用
  • 批准号:
    7842659
  • 财政年份:
    2006
  • 资助金额:
    $ 54.47万
  • 项目类别:

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