MOLECULAR SIGNALS IN PULMONARY HYPERTENSION

这个实验室的长期目标是了解其机制(S) 是导致肺动脉高压的根本原因。这项提议是一项 扩展了我们以前的形态、力学和力学的研究 分离动脉血管的药理学特性 高氧所致的肺动脉高压。《公约》的具体目标 建议的研究是：1)了解变化的分子基础 在特定的结构和收缩蛋白的含量中 描述实验模型中发生的血管重塑 2)直接测试壁张力和氧气的影响 浓缩对分离的靶蛋白的调节作用 动脉。为了实现这些目标，我们将测量合成速率和 肌动蛋白异构体、肌球蛋白、I型和III型胶原及 正常和高氧大鼠在体肺动脉弹性蛋白的表达 在体外孵育的血管节段中。我们将使用原位杂交 识别包含这些的血管壁中的细胞类型的技术 特定的mRNAs。PDGF样分子的mRNA水平的变化将是 测量并定位到特定的细胞类型，以便评估 这些效应器参与了发生的增殖性事件。我们 会将结果与形态、增殖和生化联系起来 脉管壁的特征。我们将检验假设 增加壁张力和提高氧气浓度是很重要的 启动血管重组变化的因素。这个 拟议中的实验将提供有关分子的新信息 调解血管结构和功能变化的事件，并将 提供对壁张力和氧气的直接影响的见解 肺血管重构相关参数的研究进展 高血压。

The long term goal of this laboratory is to understand the mechanism(s) underlying the development of pulmonary hypertension. The proposal is an extension of our previous investigations of the morphologic, mechanical and pharmacologic properties of isolated arterial vessels in an animal model of pulmonary hypertension induced by hyperoxia. The specific goals of the proposed research are: 1) to understand the molecular bases for alterations in the content of specific structural and contractile proteins which characterize the vascular remodeling that occurs in the experimental model and 2) to directly test the effects of wall tension and oxygen concentration on the regulation of the targeted proteins in isolated arteries. To accomplish these goals we will measure the synthesis rates and mRNA levels for actin isoforms, myosin, collagen types I and III and elastin in pulmonary arteries of normal and hyperoxic rats both in vivo and in vascular segments incubated in vitro. We will use in situ hybridization techniques to identify the cell types in the vessel wall containing these specific mRNAs. Changes in mRNA levels for PDGF-like molecules will be measured and localized to specific cell types in order to assess the involvement of these effectors in the proliferative events that occur. We will relate the results to morphologic, proliferative, and biochemical characteristics of the vessel wall. We will test the hypotheses that increased wall tension and elevated concentrations of oxygen are important factors in the initiation of changes in vascular restructuring. The proposed experiments will provide new information about the molecular events which mediate alterations in vessel structure and function and will provide insights into the direct effects of wall tension and oxygen concentration on parameters relevant to vascular restructuring in pulmonary hypertension.