COBRE: W& I HOSP OF RI: MECHANOTRANSDUCTION & LUNG ALVEOLAR DIFFERENTIATION

铜芯：W

• 批准号: 7381992
• 负责人: JUAN R SANCHEZ-ESTEBAN
• 金额: $ 22.45万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381992
• 关键词: COBRE; W&; HOSP; RI; MECHANOTRANSDUCTION

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Normal lung growth and development during fetal life are critical for extrauterine survival. Mechanical forces generated in utero by repetitive breathing movements and by fluid distension are essential to mammalian lung development. Previous studies from our laboratory showed that mechanical stretch, simulating fetal breathing movements, induces fetal type II cell maturation. Our Preliminary Studies have revealed important functions for mitogen-activated protein kinase (MAPK) signal cascades and the actin cytoskeleton in stretch-induced type II cell differentiation. We also have identified potential roles for heterotrimeric G-proteins and specific receptor tyrosine kinases, RTKs (i.e., the epidermal growth factor and insulin-like growth factor-I receptors [EGFR, IGF-IR]) as mechanosensors during alveolar development. The long-range goal of these studies is to understand cell and molecular mechanisms that transduce mechanical stretch signals into a lung differentiation program. We will test the central hypothesis that cell surface mechanosensors activate the ERK MAPK pathway and actin cytoskeletal remodeling to promote fetal epithelial cell differentiation. First, we will test the hypothesis that the EGFR and IGF-IR function as "mechanosensors" in developing distal pulmonary epithelial cells and we will determine whether stretch-induced transactivation by G-proteins is required for the mechanosensor properties. We then will test the following hypotheses: (a) Interactions between specific RTKs (EGFR, IGF-IR) and G-protein coupled receptors (GPCRs) activate ERK-dependent signaling and permit stretch-induced type II cell maturation; and (b) the proximal effector Raf-1 plays a key role in conveying mechanical signals into the ERK cascade. Finally, we will determine if direct contacts between ERK pathway effector proteins andactin-associated proteins are required. We will focus on the actin-associated protein alpha-actinin. These studies will incorporate complementary biochemical, genetic and molecular imaging te

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。胎儿时期肺的正常生长和发育对宫外存活至关重要。由重复呼吸运动和液体膨胀在子宫中产生的机械力对哺乳动物肺的发育是必不可少的。我们实验室以前的研究表明，机械拉伸模拟胎儿呼吸运动，诱导胎儿II型细胞成熟。我们的初步研究揭示了丝裂原活化蛋白激酶(MAPK)信号通路和肌动蛋白细胞骨架在拉伸诱导的II型细胞分化中的重要作用。我们还确定了异三聚体G蛋白和特异性受体酪氨酸激酶(RTK)(即表皮生长因子和胰岛素样生长因子-I受体[EGFR，IGF-IR])在肺泡发育过程中作为机械传感器的潜在作用。这些研究的长期目标是了解将机械拉伸信号转化为肺分化程序的细胞和分子机制。我们将验证中心假设，即细胞表面机械传感器激活ERK MAPK通路和肌动蛋白细胞骨架重塑以促进胎儿上皮细胞分化。首先，我们将验证EGFR和IGF-IR在远端肺上皮细胞发育过程中作为机械传感器的假设，并确定拉伸诱导的G蛋白反式激活是否是机械传感器所必需的。然后，我们将检验以下假设：(A)特定RTK(EGFR、IGF-IR)与G蛋白偶联受体(GPCRs)之间的相互作用激活ERK依赖的信号并允许拉伸诱导的II型细胞成熟；以及(B)近端效应器Raf-1在将机械信号传递到ERK级联中起关键作用。最后，我们将确定ERK通路效应蛋白和肌动蛋白相关蛋白之间是否需要直接接触。我们将重点介绍肌动蛋白相关蛋白α-肌动蛋白。这些研究将结合互补的生化、遗传和分子成像技术。