TNF-alpha to TGF-beta Signal Transduction

TNF-α 至 TGF-β 信号转导

基本信息

项目摘要

DESCRIPTION (provided by applicant): Interstitial pulmonary fibrosis (IPF) has numerous etiologies and afflicts millions of individuals worldwide. Yet, there are no effective preventive agents or therapeutic approaches. This situation is due in large part to a lack of understanding of the fundamental molecular mechanisms that mediate the fibrogenic process. In the work proposed here, we have focused on two peptide factors that have been implicated by numerous researchers as central to the development of IPF. These factors are tumor necrosis factor alpha (TNF-a) and transforming growth factor beta one (TGF-B1). Our previous work and preliminary data show that TNF-a up-regulates the expression of TGF-B1 both in vitro and in vivo, but the basic mechanisms through which TNF-a influences TGF-B1 expression remain undefined. TNF-a has been considered by many to be a "master cytokine" that controls the expression of a number of biologically relevant molecules. In as much as TGF-B1 is considered to be a primary "fibrogenic factor", we have set forth the central hypothesis that TNF-a induces TGF-B1 production by transcriptional regulation through the MEK/ERK pathway in lung cells: and the pathway of fibrogenesis mediated by TNF-a through TGF-B1 can be interrupted by specific siRNAs that mediate the degradation of transcripts that code for TNF-a, MP-1- a key component of MEK/ERK phosphorylation, and TGF-B1. Specific Aim 1 will establish MEK/ERK transduction pathways from TNF-a to TGF-B1 and the transcriptional mechanisms of expression. Aim 2 will focus on other factors that could up-regulate TGF-B1 through this same pathway; and in Aim 3, we will learn if the epithelial and mesenchymal cells in vivo in the lung exhibit the same transduction and transcriptional pathways in health and disease. These studies will provide specific targets for potential therapeutic approaches through the use of small interfering RNAs (siRNA). Thus, in Aim 4, we will show that an siRNA we have designed blocks endogenous TNF-a gene expression. We propose to use this construct as well as an siRNA that degrades MP1 (a key protein in MEK/ERK phosphorylation), and finally an siRNA that will block TGF-B1 expression, and ultimately the development of IPF in our established animal models.
描述(由申请人提供):间质性肺纤维化(IPF)有多种病因,困扰着全世界数百万人。然而,尚无有效的预防剂或治疗方法。这种情况在很大程度上是由于缺乏对介导纤维化过程的基本分子机制的了解。在这里提出的工作中,我们重点关注了两种肽因子,许多研究人员认为它们对于 IPF 的发展至关重要。这些因子是肿瘤坏死因子 α (TNF-a) 和转化生长因子 β 1 (TGF-B1)。我们之前的工作和初步数据表明,TNF-a 在体外和体内均上调 TGF-B1 的表达,但 TNF-a 影响 TGF-B1 表达的基本机制仍不清楚。 TNF-α被许多人认为是控制许多生物学相关分子表达的“主细胞因子”。由于 TGF-B1 被认为是主要的“纤维形成因子”,我们提出了中心假设,即 TNF-a 通过肺细胞中 MEK/ERK 途径的转录调节诱导 TGF-B1 的产生:并且 TNF-a 通过 TGF-B1 介导的纤维形成途径可以被介导编码转录本降解的特定 siRNA 打断。 TNF-a、MP-1(MEK/ERK 磷酸化的关键成分)和 TGF-B1。具体目标1将建立从TNF-a到TGF-B1的MEK/ERK转导途径以及表达的转录机制。目标 2 将重点关注可通过同一途径上调 TGF-B1 的其他因素;在目标 3 中,我们将了解肺体内的上皮细胞和间充质细胞在健康和疾病中是否表现出相同的转导和转录途径。这些研究将为通过使用小干扰 RNA (siRNA) 的潜在治疗方法提供特定靶点。因此,在目标 4 中,我们将证明我们设计的 siRNA 可以阻断内源性 TNF-α 基因表达。我们建议使用该构建体以及降解 MP1(MEK/ERK 磷酸化中的关键蛋白)的 siRNA,最后使用将阻断 TGF-B1 表达的 siRNA,并最终在我们建立的动物模型中阻断 IPF 的发展。

项目成果

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Arnold Ralph Brody其他文献

Arnold Ralph Brody的其他文献

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{{ truncateString('Arnold Ralph Brody', 18)}}的其他基金

TNF-alpha to TGF-beta Signal Transduction
TNF-α 至 TGF-β 信号转导
  • 批准号:
    6929935
  • 财政年份:
    2004
  • 资助金额:
    $ 24.92万
  • 项目类别:
TNF-alpha to TGF-beta Signal Transduction
TNF-α 至 TGF-β 信号转导
  • 批准号:
    7354604
  • 财政年份:
    2004
  • 资助金额:
    $ 24.92万
  • 项目类别:
Bone Marrow Derived Stromal Cells in Rat Models of Lung Injury
肺损伤大鼠模型中的骨髓衍生基质细胞
  • 批准号:
    6968004
  • 财政年份:
    2004
  • 资助金额:
    $ 24.92万
  • 项目类别:
TNF-alpha to TGF-beta Signal Transduction
TNF-α 至 TGF-β 信号转导
  • 批准号:
    7473890
  • 财政年份:
    2004
  • 资助金额:
    $ 24.92万
  • 项目类别:
TNF-alpha to TGF-beta Signal Transduction
TNF-α 至 TGF-β 信号转导
  • 批准号:
    6822801
  • 财政年份:
    2004
  • 资助金额:
    $ 24.92万
  • 项目类别:
TNF-alpha to TGF-beta Signal Transduction
TNF-α 至 TGF-β 信号转导
  • 批准号:
    7099518
  • 财政年份:
    2004
  • 资助金额:
    $ 24.92万
  • 项目类别:
Training in Lung Modular and Cell Pathobiology
肺模块和细胞病理学培训
  • 批准号:
    6592562
  • 财政年份:
    2003
  • 资助金额:
    $ 24.92万
  • 项目类别:
Training in Lung Modular and Cell Pathobiology
肺模块和细胞病理学培训
  • 批准号:
    6804510
  • 财政年份:
    2003
  • 资助金额:
    $ 24.92万
  • 项目类别:
Training in Lung Modular and Cell Pathobiology
肺模块和细胞病理学培训
  • 批准号:
    6942304
  • 财政年份:
    2003
  • 资助金额:
    $ 24.92万
  • 项目类别:
EPITHELIAL GROWTH FACTORS IN ENVIRONMENTAL LUNG DISEASE
环境性肺病中的上皮生长因子
  • 批准号:
    6389943
  • 财政年份:
    1997
  • 资助金额:
    $ 24.92万
  • 项目类别:

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