Prx homebox genes in pulmonary vascular homeostasis

描述（由申请人提供）：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子 以及显影过程中的粘附性。虽然同源异型盒基因也表达 在出生后的发育过程中，对它们的发育情况知之甚少。 调节肺血管稳态和疾病的末端功能。最近 我们实验室的工作已经确定， 配对相关的同源异型盒基因Prx 1和Prx 2在正常成人中被抑制 肺动脉（PA）。相反，这些基因表达于 外膜，然后在介质中，高血压PA，其中， 与促增殖糖蛋白腱生蛋白-C（TN-C）共定位。以来 蛋白酶对细胞外基质（ECM）的重塑对于细胞外基质的形成至关重要。 肺血管疾病的发病机制，我们研究了是否改变， 血管平滑肌细胞（SMC）与ECM的粘附调节Prx 1和Prx 2： SMC在天然I型胶原蛋白（α 2 β 1整联蛋白配体， 抑制ERK 1/2 MAPK活性）显示低水平的Prx 1和Prx 2 mRNA 表情相反，维持在变性I型胶原上的细胞（一种 活化ERK 1/2的α v β 3整联蛋白配体）显示高水平的 两种基因的表达。在功能水平上，Prx 1的表达 显著增加SMC生长和TN-C基因转录。这些发现 支持Prx基因受细胞内变化调节的一般假设。 粘附到ECM，Prx蛋白在PM重塑中发挥关键作用， 控制细胞生长和形态调节分子的表达， 包括TN-C。为了验证这一假设，我们将：（1）确定I型如何 胶原、β 3整合素和ERK 1/2 MAPK调节Prx基因及其编码的 PA外膜成纤维细胞和中膜SMC中的蛋白;（2）阐明Prx 蛋白质控制TN-C的转录，并识别其他基因靶点 与Prx蛋白相互作用的蛋白质，以及（3）确定Prx基因在 完整培养PA的外膜层影响 周围的外膜成纤维细胞和完整PA内的邻近中膜SMC。 总的来说，这些研究将确定基因和蛋白质网络， 负责增强Prx 1和Prx 2的表达，并将展示如何Prx 包括TN-C在内的基因靶标在重塑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.