TGF-ALPHA AND THE EGF RECEPTOR AND ALVEOLAR REPAIR

TGF-α 和 EGF 受体以及肺泡修复

• 批准号: 2225485
• 负责人: DAVID K MADTES
• 金额: $ 2.75万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2225485
• 关键词: adult respiratory distress syndrome; alveolar macrophages; bleomycin; cell cycle; collagen; cytokine; disease /disorder model; epidermal growth factor; gene expression; genetic regulation; genetic transcription; genetically modified animals; growth factor receptors; human subject; laboratory mouse; laboratory rat; lung injury; lung lavage; monocyte; secretion; transforming growth factors; wound healing

This proposal outlines an investigation of the role of transforming growth factor-alpha (TGF-alpha), a chemotactic factor for macrophage and epithelial cells, as well as, a mitogen for epithelial and mesenchymal cells, in the fibroproliferative response to acute lung injury. The central hypothesis is that expression of TGF-alpha and activation of the epidermal growth factor (EGF) receptor in areas of lung injury plays an important role in modulating cellular proliferation an collagen accumulation during the reparative process. The specific hypotheses are that: 1) TGF-alpha expression by alveolar macrophage and monocytes is regulated by cytokines released at sites of lung injury; 2) TGF-alpha expression by these cells is amplified by an auto-induction mechanism mediated through the EGF receptor; 3) the increased TGF-alpha mRNA levels observed in activated macrophage and monocytes is due, in part, to increased mRNA stability; 4) TGF-alpha expression is increased in the lung following acute injury; and 5) cellular proliferation, collagen accumulation and expression of fibrogenic cytokines and growth factors in response to lung injury is diminished in TGF-alpha deficient animals. Aim 1 is to characterize the regulation of TGF-alpha gene expression and protein secretion by alveolar macrophage and monocytes. Studies are planned to determine the effects of cytokines released in areas of lung injury of TGF-alpha gene transcription and protein secretion by macrophage and monocytes, to evaluate TGF-alpha mRNA stability and regulation of TGF-alpha gene conditioned medium. These studies are expected to delineate molecular and cellular mechanisms that regulate macrophage expression of TGF-alpha. Aim 2 is to define the role of TGF- alpha regulating cellular proliferation, collagen accumulation and cytokine expression in the reparative response to bleomycin induced lung injury in TGF-alpha null mutation transgenic and wild genotype mice. Aim 3 is to evaluate TGF-alpha transcription and secretion in patients with diffuse acute lung injury (ARDS) and bleomycin injured rats. These studies are planned to determine TGF-alpha activity present in these lavage fluids, and to identify the cellular location and distribution of TGF-alpha and the EGF receptor in injured lung. These studies are expected to delineate expression of TGF-alpha following lung injury in humans and to provide a framework for correlating the observations made in bleomycin injured rats and transgenic mice with the fibroproliferative response that occurs in human acute lung injury. the ultimate goal of this proposal is to establish the necessary foundation for research directed toward therapeutic manipulation of TGF-alpha expression and/or EGF receptor activation, facilitating alveolar repair.

该提案概述了对转型作用的调查 生长因子-α（TGF-α），巨噬细胞的趋化因子和 上皮细胞，以及上皮细胞和间充质细胞的有丝分裂原 细胞对急性肺损伤的纤维增殖反应。 这 中心假设是 TGF-α 的表达和 肺损伤区域的表皮生长因子 (EGF) 受体发挥着重要作用 胶原蛋白在调节细胞增殖中发挥重要作用 修复过程中的积累。 具体假设是 1) 肺泡巨噬细胞和单核细胞表达的 TGF-α 是 受肺损伤部位释放的细胞因子调节； 2) 转化生长因子-α 这些细胞的表达通过自诱导机制得到放大 通过EGF受体介导； 3) TGF-α mRNA水平增加 在活化的巨噬细胞和单核细胞中观察到的部分原因是 增加 mRNA 稳定性； 4) TGF-α表达增加 急性损伤后的肺； 5) 细胞增殖、胶原蛋白 纤维化细胞因子和生长因子的积累和表达 TGF-α缺陷动物对肺损伤的反应减弱。 目标 1 是表征 TGF-α 基因表达的调节以及 肺泡巨噬细胞和单核细胞分泌蛋白质。 研究是 计划确定肺部区域释放的细胞因子的影响 TGF-α基因转录和蛋白质分泌的损伤 巨噬细胞和单核细胞，以评估 TGF-α mRNA 稳定性和 TGF-α基因条件培养基的调节。 这些研究是 有望描述调节的分子和细胞机制 巨噬细胞表达TGF-α。 目标 2 是定义 TGF-的作用 α调节细胞增殖、胶原蛋白积累和 博来霉素诱导的肺修复反应中细胞因子的表达 TGF-α 无效突变转基因和野生基因型小鼠的损伤。 目的 图3是评估患有以下疾病的患者的TGF-α转录和分泌 弥漫性急性肺损伤（ARDS）和博来霉素损伤的大鼠。 这些 计划进行研究以确定这些物质中存在的 TGF-α 活性 灌洗液，并确定细胞位置和分布 受损肺中的 TGF-α 和 EGF 受体。 这些研究是 预计可描述肺损伤后 TGF-α 的表达 人类并提供一个框架来关联所进行的观察 在博来霉素损伤的大鼠和患有纤维增殖性的转基因小鼠中 人类急性肺损伤时发生的反应。 最终目标 该提案旨在为研究奠定必要的基础 直接针对TGF-α表达的治疗操作和/或 EGF受体激活，促进肺泡修复。