PTN FUNCTION IN INTIMAL THICKENING

描述（由申请人提供）：该提案源于我们最近发现的冠状动脉和乳腺动脉的独特基因表达谱。有广泛而令人信服的证据表明，不同动脉发生动脉粥样硬化的倾向存在潜在差异。然而，这些差异的潜在分子机制完全未被探索。我们已经生成了代表猪冠状动脉和猪乳腺动脉特异性mRNA的互惠cDNA集合。发现多营养蛋白（PTN）基因在冠状动脉特异性表达。PTN是一种多功能细胞因子，已在肿瘤中表达，并与肿瘤发生有关。然而，PTN的心血管活性尚不清楚。由于PTN表现出与血管病变相关的活性，因此这项应用是基于PTN在动脉壁的表达有助于血管病变和血管重塑的假设。本项目将通过体外和动物模型系统来描述PTN在新生内膜形成中的作用。我们拟开展相关研究，旨在确定PTN介导的血管重构的细胞机制，评估降低PTN基因表达及其受体表达的干预效果，探索PTN基因特异性的内膜增厚机制。通过研究PTN如何促进血管重塑，并确定介导PTN在血管壁活性的潜在细胞和分子机制，这一应用有望为理解特定基因如何在血管疾病的发病机制中发挥作用迈出重要的新一步。

DESCRIPTION (provided by applicant): This proposal grew out of our recent discovery of unique gene expression profiles of coronary and mammary arteries. There is extensive and compelling evidence demonstrating that there are underlying differences in propensity of different arteries to develop atherosclerosis. However, the underlying molecular mechanisms for these differences are completely unexplored. We have generated reciprocal cDNA collections of representing mRNA specific to porcine coronary vs. porcine mammary arteries. Pleiotrophin (PTN) gene was found to be specifically expressed in the coronary artery. PTN is a multifunctional cytokine that has been expressed by tumors and has been implicated in tumorigenesis. However, the cardiovascular activity of PTN remains unknown. Since PTN exhibits activities that are relevant to vascular pathologies, this application is based on the hypothesis that expression of PTN in arterial wall contributes to vascular pathologies and vascular remodeling. This project will characterize the role of PTN in neointimal formation by using in vitro and animal model systems. We propose interrelated studies that are designed to identify the cellular mechanism mediated by PTN that contributes to vascular remodeling, to evaluate the efficacy of intervention reducing PTN gene expression and its receptor expression, and to explore the PTN gene-specific mechanism of neointimal thickening. By studying how PTN contributes to vascular remodeling and identify the underlying cellular and molecular mechanism that mediates activity of PTN in the vessel wall, this application promises to take an important new step toward understanding how specific gene play a part in the pathogenesis of vascular disorders. PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains the leading cause of death in men and women in the United States; about 1.26 million Americans this year will have a new or recurrent heart attack resulting from atherothrombosis, indicating the need for new therapeutic approaches. We have recently identified a novel gene, PTN, which has biological activities that could make it an important player in cardiovascular disease. In this grant proposal, we aim to further define the role of PTN gene in vascular disease in an animal model and cultured cells with the hope that in the future, modifying PTN activity may emerge as a new therapeutic approach against vascular pathologies.