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MCP-1 induced gene expression in cardiovascular disease

MCP-1 诱导心血管疾病基因表达

基本信息

批准号：
6921433
负责人：
PAPPACHAN KOLATTUKUDY KOLATTUKUDY
金额：
$ 36万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-20 至 2007-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6921433
关键词：
apoptosis cardiac myocytes cytokine flow cytometry gene expression gene induction /repression genetically modified animals heart ventricle immunocytochemistry laboratory mouse microarray technology monocyte monocyte chemoattractant protein 1 myocardial ischemia /hypoxia myocardium polymerase chain reaction terminal nick end labeling tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): Many recent reports provide strong evidence that MCP- 1 plays a major role in the development of ischemic heart disease (IHD) that is responsible for the majority of the 5 million human heart failure cases in the US, but the underlying mechanism is not known. We postulate that MCP-1-induced gene expression changes in the monocytes and the consequent production of cytokines and other biologically active molecules, as well as possible direct effects of MCP- 1 on the major cell types in the myocardium can lead to the development of IHD. IHD probably develops as a net consequence of the interplay of these events which involve many cell types and many biologically active molecules. Therefore in vitro studies on isolated cells cannot accurately reflect the interactions involved in IND. On the other hand a genomic approach can discover the genes whose altered expression in the heart leads to the development of IHD. Such an approach, although not possible on humans, can be done on a suitable animal model. We have developed a transgenic murine model that faithfully recapitulates most features of human IRD. Use of this model has a high likelihood of discovering novel genes as illustrated by our discovery of a previously unknown MCP-1-induced protein (MCPIP). With this overall objective we propose to pursue the following specific aims: 1.) Identify gene expression changes that occur in the ventricle during IHD development induced by targeted expression of MCP 1 in the CMC of transgenic mice using gene chip technology. 2.) Determine the function of the novel MCPIP: a) Determine whether a) MCPIP expression causes cell death, b) this death is enhanced by MCP-l and its receptor CCR2, c) whether the cell death shares features characteristic of apoptosis, d) MCPIP has a transcription factor-like activity and whether structural features required for this activity are also required for the cell death-inducing activity. 3.) Assess the role of apoptosis in the development of MCP 1-induced cardiovascular disease by testing whether a) prevention of monocyte apoptosis by targeted expression of Bc12 or b) prevention of apoptosis by absence of Fas or expression of sFas in the myocytes would delay or rescue the development of the disease. The approach proposed here will identify MCP-l induced alterations in the expression of known genes not previously implicated in IHD and novel genes of unknown function that are involved in IHD. These genes are likely to reveal novel targets for intervention in IND and genes with prognostic value.

描述（由申请人提供）：许多最近的报告提供了有力的证据，证明MCP- 1在缺血性心脏病（IHD）的发展中起着重要作用，而缺血性心脏病是美国500万人心力衰竭病例中的大多数病例的原因，但其潜在机制尚不清楚。我们推测，MCP-1诱导的单核细胞基因表达的变化和随之产生的细胞因子和其他生物活性分子，以及MCP- 1对心肌中主要细胞类型的可能直接影响，可以导致IHD的发展。IHD的发展可能是这些事件相互作用的净结果，这些事件涉及许多细胞类型和许多生物活性分子。因此，在离体细胞的体外研究不能准确地反映参与IND的相互作用。另一方面，基因组方法可以发现基因的表达改变，在心脏中导致IHD的发展。这种方法虽然在人类身上不可能，但可以在合适的动物模型上进行。我们已经开发了一种转基因小鼠模型，忠实地概括了人类IRD的大部分特征。使用这种模型有很高的可能性发现新的基因，如我们发现的一个以前未知的MCP-1诱导蛋白（MCPIP）。根据这一总体目标，我们建议实现以下具体目标：1.使用基因芯片技术识别转基因小鼠CMC中MCP 1靶向表达诱导的IHD发展期间心室中发生的基因表达变化。2.）的情况。确定新MCPIP的功能：a）确定a）MCPIP表达是否引起细胞死亡，B）这种死亡是否被MCP-1及其受体CCR 2增强，c）细胞死亡是否具有细胞凋亡的特征，d）MCPIP是否具有转录因子样活性，以及这种活性所需的结构特征是否也是细胞死亡诱导活性所需的。3.）第三章通过检测a）通过靶向表达Bc 12预防单核细胞凋亡或B）通过在肌细胞中缺乏Fas或表达sFas预防凋亡是否会延迟或挽救疾病的发展来评估细胞凋亡在MCP 1诱导的心血管疾病的发展中的作用。本文提出的方法将鉴定MCP-1诱导的先前未涉及IHD的已知基因表达的改变和涉及IHD的未知功能的新基因。这些基因可能揭示IND干预的新靶点和具有预后价值的基因。