WNT5a Signaling in Stage Specific Alveolar Epithelial Cell Differentiation

特定阶段肺泡上皮细胞分化中的 WNT5a 信号传导

• 批准号: 10116775
• 负责人: CHANGGONG LI
• 金额: $ 4.09万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116775
• 关键词: Accreditation; Alveolar; Area; Basic Science; Biomedical Research; Birth; Bronchopulmonary Dysplasia; Ca(2+)-Calmodulin Dependent Protein Kinase; Cell Differentiation process; Communities; Data; Data Analyses; Defect; Development; Ensure; Epithelial Cells; Ethnic group; Experimental Designs; Failure; Gene Expression Profiling; Generations; Genetic Engineering; Genetic Models; Goals; Grant; Health; Hispanics; Immunohistochemistry; In Vitro; Individual; Learning; Life; Ligands; Lung; Lung diseases; Mediator of activation protein; Medical; Mentors; Methods; Molecular; Mus; Mutant Strains Mice; Myofibroblast; Names; National Heart, Lung, and Blood Institute; Organ; Pathway Analysis; Pathway interactions; Premature Infant; Process; Proteins; RNA; ROR1 gene; Reading; Research; Role; Science; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Structure; Supervision; Technical Expertise; Technology; Testing; Thinking; Tissues; Training; Transgenic Mice; Underrepresented Groups; Universities; alveolar epithelium; analytical method; base; calmodulin-dependent protein kinase II; career; cell type; design; effective therapy; epithelial stem cell; experimental study; fetal; gain of function; gain of function mutation; improved; in vivo; in vivo Model; interest; loss of function; lung maturation; meetings; member; novel therapeutics; parent grant; progenitor; receptor; respiratory distress syndrome; skills; therapeutic target; training opportunity; training project

ABSTRACT Maturation of fetal organs to support life after birth is a significantly vital process. However, in most cases, this process is poorly investigated/understood. In the lung, failure in maturation is a significant health problem. In preterm infants, it can cause Respiratory Distress Syndrome (RDS) and BronchoPulmonary Dysplasia (BPD). We have found that loss-of-function for a non-canonical WNT ligand, WNT5a inhibits lung maturation. Two key defects include inhibition of alveolar type 1 epithelial cell (AEC1) differentiation and alveolar myofibroblast (AMF) differentiation. Importantly, the converse is also true; Wnt5a gain-of-function promotes lung maturation & AEC1 differentiation. In additional preliminary studies, we show that loss-of- function of WNT5a receptors, ROR1 and ROR2, results in similar defects in lung maturation as in WNT5a loss-of-function. WNT5a activates Calcium/calmodulin-dependent protein kinase II (CaMKII) an important cytoplasmic signal transduction molecule. Inhibiting CaMKII also disrupts lung maturation. Based on the collective preliminary findings, we propose the following hypothesis: HYPOTHESIS: WNT5a-ROR signaling is a key regulator of lung maturation. This pathway controls the structural, cellular and molecular steps that ultimately contribute to the formation of functional lungs. In this application, we will focus on AEC1 and AMF differentiation, as two key cellular mechanisms controlled by WNT5a during lung maturation. Multiple tissue specific, conditional in vivo models that target Wnt5a and Rors in AEC and AMF during lung maturation will be used to determine their cell-type specific functions in saccular and alveolar stages. The studies will also determine the role of CaMKII as WNT5a mediator. We propose the following Specific Aims. Specific Aim 1. To Determine the Function of WNT5a Signaling in AEC During Lung Maturation. Specific Aim 2. To Determine the Function of WNT5a Signaling in AMF During Lung Maturation. Specific Aim 3. To Determine the Role of CaMKII as a Downstream Intracellular Mediator of WNT5a Signaling in Lung Maturation. Health Relevance: Lung maturation is an existential requirement for surviving after birth. If successful, the results of this research will likely have a meaningful impact on understanding the mechanisms underlying lung maturation, which may help in development of more effective & novel therapies for lung diseases in premature infants. Determining the role of WNT5a, RORs & CaMKII in lung maturation could further suggest therapeutic targets at different levels of signal transduction & may allow for more selective modulation of this process.

抽象的 胎儿器官的成熟以支持出生后的生命是一个非常重要的过程。然而，在大多数情况下， 这个过程的调查/理解很少。在肺部，成熟失败是一个重要的健康问题 问题。对于早产儿，它可能导致呼吸窘迫综合征（RDS）和支气管肺疾病 发育不良（BPD）。 我们发现非经典 WNT 配体 WNT5a 的功能丧失会抑制肺成熟。 两个关键缺陷包括抑制肺泡 1 型上皮细胞 (AEC1) 分化和肺泡 肌成纤维细胞（AMF）分化。重要的是，反之亦然。 Wnt5a 功能获得性 促进肺成熟和 AEC1 分化。在其他初步研究中，我们表明损失 - WNT5a 受体 ROR1 和 ROR2 的功能导致与 WNT5a 类似的肺成熟缺陷 功能丧失。 WNT5a 激活钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) 细胞质信号转导分子。抑制 CaMKII 也会破坏肺成熟。基于 综合初步调查结果，我们提出以下假设： 假设：WNT5a-ROR 信号传导是肺成熟的关键调节因子。该通路控制 最终有助于形成功能性肺的结构、细胞和分子步骤。 在此应用中，我们将重点关注 AEC1 和 AMF 分化，这是两种关键的细胞机制 在肺成熟过程中由 WNT5a 控制。多种组织特异性、有条件的体内模型 肺成熟期间 AEC 和 AMF 中的目标 Wnt5a 和 Rors 将用于确定其细胞类型 囊状和肺泡阶段的特定功能。这些研究还将确定 CaMKII 的作用： WNT5a 介体。我们提出以下具体目标。 具体目标 1. 确定 WNT5a 信号传导在肺成熟过程中 AEC 中的功能。 具体目标 2. 确定肺成熟过程中 AMF 中 WNT5a 信号传导的功能。 具体目标 3. 确定 CaMKII 作为下游细胞内介导物的作用 肺成熟过程中的 WNT5a 信号传导。 健康相关性：肺成熟是出生后生存的必要条件。如果成功的话， 这项研究的结果可能会对理解其机制产生有意义的影响 潜在的肺部成熟，这可能有助于开发更有效和新颖的肺部疗法 早产儿疾病。确定 WNT5a、ROR 和 CaMKII 在肺成熟中的作用可以 进一步提出不同信号转导水平的治疗靶点，并可能允许更具选择性 这个过程的调制。