Hippo Signaling In Lung Development And Injury Repair

河马信号在肺部发​​育和损伤修复中的作用

• 批准号: 9122853
• 负责人: Leah Brennan Nantie
• 金额: $ 5.62万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122853
• 关键词: Accounting; Address; Adhesions; Adult; Alveolar; Alveolar Cell; Apical; Area; Behavior; Biology; Cell Adhesion; Cell Differentiation process; Cell Polarity; Cell Proliferation; Cells; Choices and Control; Clinical; Complex; Congenital Disorders; Cues; Data; Defect; Development; Developmental Process; Disease; Employee Strikes; Environment; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Extracellular Matrix; Gases; Genes; Genetic; Health; Heart; Human; Hyperplasia; Infant; Influenza; Injury; Lead; Live Birth; Liver; Lung; Morphogenesis; Mutation; Nuclear; Organ; Organ Size; Pathway interactions; Patients; Phenotype; Phosphotransferases; Population; Process; Property; Respiratory Failure; Respiratory System; Respiratory distress; Role; SHH gene; Signal Pathway; Signal Transduction; Stem cells; Surface; System; Testing; Therapeutic Intervention; Translating; behavior influence; cell behavior; extracellular; injury and repair; insight; keratin 5; lung development; lung injury; lung repair; malformation; migration; mutant; novel; overexpression; premature; prenatal; progenitor; public health relevance; pulmonary hypoplasia; repaired; respiratory; transcription factor

 DESCRIPTION (provided by applicant): Proper development of the respiratory system is crucial to generate adequate surface area for gas exchange. Disruption of respiratory developmental processes can lead to diseases such as pulmonary hypo- or hyperplasia (1 in 4,000 live births) or cystadenomatoid malformations, all of which have serious consequences for human health. Several factors have been identified that lead to respiratory system defects in humans, including mutations in SHH and TTF-1. However, patients with these mutations account for only a small subset of infants born with respiratory distress or respiratory failure, making it crucial to uncover novel signaling pathways important in lung development. Furthermore, these or similar pathways are likely to be reactivated during lung injury repair making them possible targets of clinical therapies. The Hippo signaling pathway is a newly discovered evolutionarily conserved mechanism that regulates organ size, proliferation and cell differentiation in the development of many systems. My preliminary data shows that loss of Lats, an upstream Hippo kinase, leads unexpectedly to smaller lung size and impaired branching morphogenesis. Additionally, Lats mutants have premature expression of type 1 alveolar epithelial cell markers. From these data, I hypothesize the Hippo pathway controls lung epithelial cell behavior by influencing key factors involved in branching morphogenesis and alveolar cell differentiation. This hypothesis will be addressed by pursuing two specific aims: 1) Determine how Hippo signaling controls lung branching morphogenesis and 2) determine how Hippo signaling regulates alveolar epithelial cell differentiation. In each of these proposed aims, I will analyze Hippo pathway mutants to determine the contribution of this pathway in regulating epithelial progenitor behavior in the prenatal and adult lung.

 描述（由申请人提供）：呼吸系统的正常发育对于产生足够的气体交换表面积至关重要。呼吸发育过程的破坏可能导致肺发育不全或肺增生（每 4,000 名活产婴儿中就有 1 人）或囊腺瘤样畸形等疾病。 ，所有这些都对人类健康产生严重后果。已确定导致人类呼吸系统缺陷的多种因素，其中包括 SHH 和 TTF-1 突变，但仅具有这些突变的患者。一小部分出生时患有呼吸窘迫或呼吸衰竭的婴儿，因此发现对肺部发育至关重要的新信号通路至关重要。此外，这些或类似的通路可能在肺损伤修复过程中重新激活，从而使它们成为临床治疗的目标。信号通路是一种新发现的进化保守机制，在许多系统的发育过程中调节器官大小、增殖和细胞分化。我的初步数据表明，上游 Hippo 激酶 Lats 的缺失会意外地导致肺尺寸变小和分支形态发生受损。此外， Lats 突变体具有 1 型肺泡上皮细胞标记物的过早表达，从这些数据中，我发现 Hippo 通路通过影响分支形态发生和肺泡细胞分化中涉及的关键因素来控制肺上皮细胞行为。 ： 1) 确定 Hippo 信号如何控制肺分支形态发生，2) 确定 Hippo 信号如何调节肺泡上皮细胞分化 在每个提出的目标中， 我将分析 Hippo 通路突变体，以确定该通路在调节产前和成年肺部上皮祖细胞行为中的贡献。