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TNF-alpha to TGF-beta Signal Transduction

TNF-α 至 TGF-β 信号转导

基本信息

批准号：
7473890
负责人：
Arnold Ralph Brody
金额：
$ 25.78万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7473890
关键词：
Adenoviruses Animal Model Animals Asbestos Autopsy Biological Assay Biopsy Cell Line Cells Chronic Code Condition Data Development Disease Disease Progression Dominant-Negative Mutation Electrophoretic Mobility Shift Assay Endothelin Epithelial Epithelial Cells Etiology Exhibits Fibroblasts Gene Expression Genes Genetic Transcription Growth Factor Health Human In Vitro Individual Inflammation Knockout Mice Laboratories Learning Lung Lung diseases MAP2K1 gene MAPK3 gene MEKs Mediating Mediator of activation protein Mesenchymal Messenger RNA Molecular Mus Nuclear Numbers Organ Pathway interactions Peptides Phosphorylation Platelet-Derived Growth Factor Play Preventive Process Production Protein Overexpression Proteins Pulmonary Fibrosis Purpose RNA Interference Reporter Research Personnel Role Run-On Assays Signal Pathway Signal Transduction Signal Transduction Pathway Small Interfering RNA TNF gene Testing Therapeutic Therapeutic Agents Tissues Transcript Transcriptional Regulation Transforming Growth Factor beta Treatment Protocols Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Up-Regulation Work cell type cytokine design fibrogenesis human TNF protein in vivo inhibitor/antagonist interstitial mRNA Stability macrophage membrane-associated placental tissue protein 1 programs promoter research study transcription factor vector

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，困扰着全球数百万人。然而，没有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理解。在这里提出的工作中，我们重点关注了两种肽因子，这两种肽因子被许多研究人员认为是IPF发展的核心。这些因子是肿瘤坏死因子α（TNF-α）和转化生长因子β 1（TGF-β 1）。我们的前期工作和初步数据表明，TNF-α在体外和体内均上调TGF-β 1的表达，但TNF-α影响TGF-β 1表达的基本机制尚不清楚。许多人认为TNF-α是控制许多生物学相关分子表达的“主细胞因子”。由于TGF-β 1被认为是主要的“纤维化因子”，我们提出了TNF-α通过肺细胞中MEK/ERK途径的转录调节诱导TGF-β 1产生的中心假设：并且由TNF-α通过TGF-β 1介导的纤维形成途径可以被介导编码TNF-α的转录物降解的特异性siRNA中断，MP-1-MEK/ERK磷酸化的关键组分，和TGF-β 1。Specific Aim 1将建立从TNF-α到TGF-β 1的MEK/ERK转导途径和表达的转录机制。目标2将集中在其他因素，可以上调TGF-β 1通过这一相同的途径;在目标3中，我们将了解，如果在肺中的上皮细胞和间充质细胞在体内表现出相同的转导和转录途径在健康和疾病。这些研究将通过使用小干扰RNA（siRNA）为潜在的治疗方法提供特异性靶点。因此，在目标4中，我们将展示我们设计的siRNA阻断内源性TNF-α基因表达。我们建议使用这种构建体以及降解MP 1（MEK/ERK磷酸化中的关键蛋白）的siRNA，最后是阻断TGF-β 1表达的siRNA，并最终在我们建立的动物模型中阻断IPF的发展。