Laminin Binding Integrins in Lung Development

肺发育中的层粘连蛋白结合整合素

• 批准号: 10064461
• 负责人: Erin J Plosa
• 金额: $ 8.65万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064461
• 关键词: Address; Adhesions; Adult; Alveolar; Avidity; Basement membrane; Behavior; Binding; Birth; Bulla; Cell Survival; Cell physiology; Collagen; Data; Defect; Disease; Embryo; Epidermolysis Bullosa; Epithelial; Epithelial Cells; Epithelium; Event; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Fetal Lung; Goals; Growth; Health; Homeostasis; Human; Hyperplasia; Impairment; Individual; Injury; Integral Membrane Protein; Integrin Binding; Integrins; Kidney; Kidney Diseases; Laminin; Laminin Receptor; Lead; Ligand Binding; Ligands; Lung; Lung diseases; Mammals; Mammary gland; Mechanoreceptors; Minor; Molecular; Morphogenesis; Mus; Mutation; Neonatal; Organ; Organogenesis; Pathway interactions; Patients; Play; Process; Pulmonary Emphysema; Regulation; Reporting; Research; Respiratory Failure; Role; Signal Pathway; Signal Transduction; Skin; Speed; Structure; Structure of respiratory epithelium; Submandibular gland; Suggestion; Testing; Time; Tissues; Transgenic Mice; Work; airway obstruction; alveolar epithelium; alveolar homeostasis; cell behavior; defined contribution; lung development; microdeletion; migration; novel strategies; pressure; programs; pulmonary hypoplasia; receptor; repaired; response; response to injury; single-cell RNA sequencing; skin disorder

PROJECT SUMMARY The overall goal of our research program is to define how cell-extracellular matrix (ECM) interactions regulate lung development and alveolar homeostasis in health and disease. Epithelial cells connect with the surrounding ECM through integrins, transmembrane protein receptors comprised of an a and b subunit. Integrins are required for signaling between epithelial cells and the ECM and regulate critical cell processes, such as adhesion, migration, proliferation, differentiation and cell survival. Laminin is one of the major components of the lung basement membrane, a specialized ECM structure. Laminin binding integrins are required for organogenesis in other branched organs such as the kidney, mammary gland, and submandibular gland, but are relatively understudied in the lung. Integrins are expressed in a temporally and spatially specific manner that influences their ECM ligand binding avidity. The precise laminin-integrin interactions that regulate fetal lung development are currently unknown. From our preliminary work, we have identified a3b1 and a6b1 as the critical integrins in lung development. Our murine deletion of a6 integrin in the lung epithelium demonstrates a critical role in early lung branching morphogenesis. New airways branch at pressure points, where epithelial cells must stop and pivot to advance airway growth in a new direction. In their role as mechanoreceptors, integrins are perfectly poised to direct the speed and direction of epithelial growth. Integrins also signal changes in the alveolar microenvironment and influence epithelial behavior. Deletion of a3 in the murine lung results in sacculation, alveolarization, and epithelial differentiation defects. Epithelial differentiation is required for proper alveolarization and the epithelial response to injury. We have previously shown that epithelial b1 integrin, binding partner to a3 integrin, is required for the normal epithelial response after injury. Thus, in this proposal, we will test the hypothesis that a6b1 integrin is the dominant laminin receptor for regulation of branching morphogenesis, whereas a3b1 is required for alveolarization. AIM 1: Determine the specific roles for laminin binding integrins in branching morphogenesis. AIM 2: Define the role of laminin binding integrins during sacculation and alveolarization.

项目摘要 我们的研究计划的总体目标是定义细胞 - 触觉基质（ECM）的相互作用如何调节 健康与疾病中的肺发育和肺泡稳态。上皮细胞与 通过整合素围绕ECM，由A和B亚基组成的跨膜蛋白受体。 需要整合素才能在上皮细胞和ECM之间发出信号，并调节关键细胞过程， 例如粘附，迁移，增殖，分化和细胞存活。层粘连蛋白是主要的 肺基底膜的成分，一种专门的ECM结构。层粘连蛋白结合蛋白是 在其他分支器官（例如肾脏，乳腺和下颌）等其他分支器官中的器官发生所需 腺体，但在肺部相对研究。整合素在时间和空间上表达 影响其ECM配体结合亲和力的方式。调节的精确层粘连蛋白 - 整合素相互作用 胎儿肺发育目前尚不清楚。从我们的初步工作中，我们确定了A3B1和A6B1 作为肺发育中的关键整合素。我们在肺上皮中A6整合素的鼠缺失 在早期肺分支形态发生中表现出关键作用。新气道分支在压力点， 上皮细胞必须停止并旋转以朝着新方向提高气道生长。在他们的角色 机械感受器，整联蛋白完美地指导上皮生长的速度和方向。 整联蛋白还会信号在肺泡微环境中变化并影响上皮行为。删除A3 在鼠中，肺部导致肺泡，牙槽化和上皮分化缺陷。上皮 适当的牙槽化和对损伤的上皮反应需要分化。我们以前有 表明正常上皮反应需要上皮B1整合素，与A3整合素的结合伴侣 受伤后。因此，在此提案中，我们将检验以下假设：A6B1整合素是主要的层粘连蛋白 调节分支形态发生的受体，而牙槽化需要A3B1。 目标1：确定层粘连蛋白结合素在分支形态发生中的特定作用。 AIM 2：定义层粘连蛋白结合素在囊肿和肺泡化过程中的作用。