VASCULAR CELL DIVERSITY IN PULMONARY HYPERTENSION

肺动脉高压中的血管细胞多样性

基本信息

批准号：
6202221
负责人：
ROBERT P. MECHAM
金额：
$ 20.75万
依托单位：
BARNES-JEWISH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2000-08-31
项目状态：
已结题

项目摘要

This project aims to characterize vascular smooth muscle cell (SMC) diversity in the pulmonary circulation as a function of development and injury. Using in situ hybridization to investigate matrix protein synthesis by cells in normal and diseased vessels, we discovered a cellular complexity that required a reconsideration of the widely held concept that the vessel wall contains a homogenous population of SMCs. The phenotypic diversity we observed dictates that to understand the cellular mechanisms associated with vascular remodeling in pulmonary hypertension, a more detailed characterization of the diverse cell populations is required. Thus, one of our objectives in this renewal is to explore the possibility that different smooth muscle cell types make unique contributions to the disease processes associated with pulmonary hypertension. In this context, we propose to investigate whether elastin gene expression provides a marker to identify the different smooth muscle phenotypes. We will also utilize differential cloning to identify genes that are unique to the hypertensive state and determine expression patterns of these genes in normal and injured pulmonary arteries. To properly interpret phenotypic modulation in response to injury, however, we must first understand the normal developmental changes a cell is programmed to undergo. Therefore, another objective will be to characterize cell phenotypes in pulmonary arteries and veins in development, focusing on the elastin phenotype. Elastin is an important vascular protein in its own right but its organization into an elastic fiber requires several other proteins that make up the microfibrils. It is now clear that the elastin phenotype is much more complex than simply elastin production. An important objective of this proposal is to utilize newly developed reagents for microfibrillar proteins to develop a more complete characterization of the elastin phenotype in vascular cells. Understanding how these components of the elastic fiber are regulated in the developing pulmonary vessel is critical to understanding their expression in vascular repair.

该项目旨在表征血管平滑肌细胞（SMC）肺循环的多样性作为发育和发育的函数受伤。使用原位杂交研究基质蛋白通过正常和患病血管中的细胞合成，我们发现了细胞的复杂性需要重新考虑广泛持有的观点血管壁含有同质的 SMC 群的概念。这我们观察到的表型多样性表明，要了解细胞与肺动脉高压血管重塑相关的机制，不同细胞群的更详细特征是必需的。因此，我们这次更新的目标之一是探索不同类型的平滑肌细胞具有独特的可能性对肺相关疾病过程的贡献高血压。在这种情况下，我们建议研究弹性蛋白是否基因表达提供了识别不同平滑肌的标记表型。我们还将利用差异克隆来鉴定基因是高血压状态所特有的并决定表达这些基因在正常和受损肺动脉中的模式。为了正确解释针对损伤的表型调节，然而，我们必须首先了解细胞的正常发育变化被编程为经历。因此，另一个目标是表征肺动脉和静脉的细胞表型发育，重点关注弹性蛋白表型。弹性蛋白是一种重要的血管蛋白本身，但其组织成弹性纤维需要几种其他蛋白质来构成微纤维。这是现在清楚，弹性蛋白表型比简单的要复杂得多弹性蛋白的产生。该提案的一个重要目标是利用新开发的微纤维蛋白试剂可开发更多血管细胞弹性蛋白表型的完整表征。了解弹性纤维的这些成分是如何调节的发育中的肺血管对于理解其功能至关重要血管修复中的表达。