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

铜芯：W

• 批准号: 7610525
• 负责人: JUAN R SANCHEZ-ESTEBAN
• 金额: $ 21.32万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610525
• 关键词: Actins; Alveolar; Biochemical Genetics; Breathing; Cell Differentiation process; Cell Maturation; Cell surface; Computer Retrieval of Information on Scientific Projects Database; Cytoskeleton; Development; Distal; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial Cells; Funding; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Grant; Growth and Development function; Heterotrimeric GTP-Binding Proteins; Imaging Techniques; Institution; Insulin-Like-Growth Factor I Receptor; Laboratories; Life; Liquid substance; Lung; Mechanics; Mitogen-Activated Protein Kinases; Molecular; Movement; Pathway interactions; Play; Property; Proteins; Range; Receptor Protein-Tyrosine Kinases; Research; Research Personnel; Resources; Role; Signal Transduction; Simulate; Source; Stretching; Testing; Transactivation; Type II Epithelial Receptor Cell; United States National Institutes of Health; alpha Actinin; fetal; in utero; lung development; molecular imaging; programs

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 techniques.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 胎儿时期正常的肺部生长和发育对于宫外生存至关重要。在子宫内通过重复呼吸运动和液体膨胀产生的机械力对于哺乳动物的肺部发育至关重要。我们实验室之前的研究表明，模拟胎儿呼吸运动的机械拉伸可诱导胎儿 II 型细胞成熟。我们的初步研究揭示了丝裂原激活蛋白激酶 (MAPK) 信号级联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功能。我们还确定了异三聚体 G 蛋白和特定受体酪氨酸激酶、RTK（即表皮生长因子和胰岛素样生长因子 I 受体 [EGFR、IGF-IR]）作为肺泡发育过程中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变成肺分化程序的细胞和分子机制。我们将测试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的中心假设。首先，我们将测试 EGFR 和 IGF-IR 在发育中的远端肺上皮细胞中充当“机械传感器”的假设，并且我们将确定机械传感器特性是否需要 G 蛋白拉伸诱导的反式激活。然后，我们将测试以下假设：（a）特定 RTK（EGFR、IGF-IR）和 G 蛋白偶联受体（GPCR）之间的相互作用激活 ERK 依赖性信号传导并允许拉伸诱导的 II 型细胞成熟； (b) 近端效应器 Raf-1 在将机械信号传递到 ERK 级联中起着关键作用。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。我们将重点关注肌动蛋白相关蛋白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。