Prx homebox genes in pulmonary vascular homeostasis

描述(申请人提供)：同源框基因编码转录 控制细胞生长、分化、凋亡的局部模式的因素 和发育过程中的粘附性。虽然同源盒基因也表达了 在出生后的发育过程中，对它们的了解相对较少 调节在肺血管动态平衡和疾病中的作用。近期 我们实验室的工作已经确定了两个表达 成对的同源异型盒基因Prx1和Prx2在正常成人中被抑制 肺动脉(PA)。相比之下，这些基因在 外膜，然后在中层，在那里他们 与促增殖糖蛋白Tn-C(TN-C)共定位。自.以来 蛋白水解酶对细胞外基质(ECM)的重塑是 肺血管疾病的发病机制，我们调查了 血管平滑肌细胞(SMC)与ECM的黏附调节Prx1和Prx2： 在天然I型胶原(一种α2beta1整合素配体， 抑制ERK1/2 MAPK活性)显示低水平的Prx1和Prx2 mRNA 表情。相反，细胞维持在变性的I型胶原上(和 αvbeta3整合素配体激活ERK1/2)显示高水平的 两个基因的表达。在功能水平上，PRX1的表达 显著促进SMC生长和TN-C基因转录。这些发现 支持Prx基因受细胞变化调控的普遍假设 与ECM的粘附性，以及Prx蛋白在PM重塑中的关键作用 控制细胞生长和形态调节分子的表达， 包括TN-C。为了检验这一假设，我们将：(1)确定类型I如何 胶原蛋白、β3整合素和ERK1/2 MAPKs调控Prx基因及其编码 PA外膜成纤维细胞和中膜SMC中的蛋白质；(2)阐明PRX是如何 蛋白质控制TN-C的转录，并识别其他基因靶点 与Prx蛋白相互作用，以及(3)确定Prx基因如何在 完整培养的PAS的外膜层影响PAS的行为 在完整的PAS内环绕外膜成纤维细胞和邻近的内侧SMC。 总的来说，这些研究将确定基因和蛋白质网络是 负责增强Prx1和Prx2的表达，并将演示Prx如何 基因靶点，包括TN-C，在重塑的PA内受到控制。

DESCRIPTION (provided by applicant): Homeobox genes encode transcription factors that control local patterns of cell growth, differentiation, apoptosis and adhesion during development. Although homeobox genes are also expressed during post-natal development, relatively little is known about their regulation end functions in pulmonary vascular homeostasis and disease. Recent work in our laboratory has established that the expression of two paired-related homeobox genes, Prx1 and Prx2, is suppressed in normal adult pulmonary arteries (PAs). In contrast, these genes are expressed in the adventitia, and thereafter in the media, of hypertensive PAs where they co-localize with the pro-proliferative glycoprotein tenascin-C (TN-C). Since remodeling of the extracellular matrix (ECM) by proteases is critical to the pathogenesis of pulmonary vascular disease, we investigated whether changes in vascular smooth muscle cell (SMC) adhesion to the ECM regulate Prx1 and Prx2: SMCs cultured on native type I collagen (an alpha2beta1 integrin ligand that suppresses ERK1/2 MAPK activity) showed low levels of Prx1 and Prx2 mRNA expression. In contrast, cells maintained on denatured type I collagen (an alphavbeta3 integrin ligand that activates ERK1/2) showed high levels of expression of both genes. At a functional level, expression of Prx1 significantly increased SMC growth and TN-C gene transcription. These findings support the general hypotheses that Prx genes are regulated by changes in cell adhesion to the ECM, and that Prx proteins play key roles in remodeling PM by controlling cell growth and the expression of morphoregulatory molecules, including TN-C. To test this hypothesis, we will: (1) Determine how type I collagen, beta3 integrins and ERK1/2 MAPKs regulate Prx genes and their encoded proteins in PA adventitial fibroblasts and medial SMCs; (2) Elucidate how Prx proteins control the transcription of TN-C, and identify other gene targets that interact with Prx proteins, and (3) Ascertain how Prx gene expression in the adventitial layer of intact cultured PAs influences the behavior of surrounding adventitial fibroblasts and adjacent medial SMCs within intact PAs. Collectively, these study will identify gene and protein networks that are responsible for enhanced Prx1 and Prx2 expression, and will demonstrate how Prx gene targets, including TN-C, are controlled within remodeling PAs.