MCP-1 induced gene expression in cardiovascular disease

描述（由申请人提供）：最近的许多报告提供了强有力的证据，表明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（IHD）是美国500万人类心力衰竭病例中大多数的原因，但其潜在机制尚不清楚。我们推测，MCP-1诱导单核细胞基因表达的改变，以及由此产生的细胞因子和其他生物活性分子，以及MCP-1对心肌主要细胞类型的可能直接影响，可导致IHD的发生。IHD可能是这些涉及许多细胞类型和许多生物活性分子的事件相互作用的净结果。因此，在离体细胞上的体外研究不能准确地反映IND所涉及的相互作用。另一方面，基因组方法可以发现在心脏中表达改变导致IHD发展的基因。这种方法虽然在人类身上不可行，但可以在合适的动物模型上实现。我们已经开发了一种转基因小鼠模型，忠实地再现了人类IRD的大部分特征。我们发现了一种以前未知的mcp -1诱导蛋白（MCPIP），利用这种模型发现新基因的可能性很高。有了这个总体目标，我们建议追求以下具体目标：1)利用基因芯片技术鉴定转基因小鼠CMC中靶向表达mcp1诱导IHD发生时脑室内基因表达的变化。2)。确定新型MCPIP的功能：a)确定a) MCPIP表达是否导致细胞死亡，b)这种死亡被mcp - 1及其受体CCR2增强，c)细胞死亡是否具有细胞凋亡的特征，d) MCPIP具有转录因子样活性，这种活性所需的结构特征是否也是细胞诱导死亡活性所必需的。3)。通过测试a)通过靶向表达Bc12预防单核细胞凋亡或b)通过肌细胞中缺乏Fas或表达sFas预防细胞凋亡是否会延缓或挽救疾病的发展，评估细胞凋亡在mcp1诱导的心血管疾病发展中的作用。本文提出的方法将确定mcp - 1诱导的与IHD无关的已知基因表达的改变，以及与IHD相关的功能未知的新基因。这些基因可能为IND的干预提供新的靶点和具有预后价值的基因。

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.