WNT5a Regulates Lung Maturation

WNT5a 调节肺成熟

基本信息

批准号：
10367986
负责人：
CHANGGONG LI
金额：
$ 46.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-06 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10367986
关键词：
Address Adult Air Alveolar Alveolar Cell Biological Process Birth Blood capillaries Breathing Bronchopulmonary Dysplasia Ca(2+)-Calmodulin Dependent Protein Kinase Cell Differentiation process Cell Polarity Cell Shape Cells Data Defect Development Distal Embryo Epithelial Cells FGF10 gene Gases Gene Targeting Goals Health Ions Knock-out Lead Life Ligands Lung Lung diseases Mediating Mediator of activation protein Modeling Molecular Morphogenesis Mutagenesis Myofibroblast Names Neonatal Organ Organism Pathway interactions Phase Phase Transition Phenotype Premature Infant Process Publications ROR1 gene Regulation Reporting Research Respiratory Failure Role SHH gene Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Sum Thinness Time Tissues WNT Signaling Pathway alveolar epithelium base calmodulin-dependent protein kinase II cell fate specification cell type early onset effective therapy fetal gain of function in utero in vivo Model knowledge base loss of function lung development lung maturation member migration novel novel therapeutics postnatal receptor respiratory respiratory distress syndrome therapeutic target

Address Adult Air Alveolar Alveolar Cell Biological Process Birth Blood capillaries Breathing Bronchopulmonary Dysplasia Ca(2+)-Calmodulin Dependent Protein Kinase Cell Differentiation process Cell Polarity Cell Shape Cells Data Defect Development Distal Embryo Epithelial Cells FGF10 gene Gases Gene Targeting Goals Health Ions Knock-out Lead Life Ligands Lung Lung diseases Mediating Mediator of activation protein Modeling Molecular Morphogenesis Mutagenesis Myofibroblast Names Neonatal Organ Organism Pathway interactions Phase Phase Transition Phenotype Premature Infant Process Publications ROR1 gene Regulation Reporting Research Respiratory Failure Role SHH gene Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Sum Thinness Time Tissues WNT Signaling Pathway alveolar epithelium base calmodulin-dependent protein kinase II cell fate specification cell type early onset effective therapy fetal gain of function in utero in vivo Model knowledge base loss of function lung development lung maturation member migration novel novel therapeutics postnatal receptor respiratory respiratory distress syndrome therapeutic target

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项目摘要

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.

抽象的胎儿器官在出生后维持生命的成熟是一个至关重要的过程。但是，在大多数情况下，该过程的调查/理解很少。在肺中，成熟失败是一个重大健康状况问题。在早产儿中，它可能导致呼吸窘迫综合征（RDS）和支气管肺发育不良（BPD）。我们发现，非典型Wnt配体的功能丧失，Wnt5a抑制肺部成熟。两个关键缺陷包括抑制牙槽1型上皮细胞（AEC1）分化和肺泡肌纤维细胞（AMF）分化。重要的是，匡威也是正确的。 WNT5A功能收益促进肺部成熟和AEC1分化。在其他初步研究中，我们表明 - Wnt5a受体ROR1和ROR2的功能导致肺部成熟与Wnt5a相似的缺陷功能丧失。 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也破坏了肺部成熟。基于集体初步发现，我们提出以下假设：假设：WNT5A-ROR信号传导是肺部成熟的关键调节剂。此途径控制结构，细胞和分子步骤最终导致功能性肺的形成。在此应用中，我们将重点放在AEC1和AMF分化上，作为两个关键的细胞机制在肺部成熟过程中由Wnt5a控制。多个组织特异性的条件体内模型肺部成熟过程中AEC和AMF中的靶Wnt5a和ROR将用于确定其细胞类型囊和肺泡阶段的特定功能。研究还将确定Camkii的作用 WNT5A调解人。我们提出以下特定目标。具体目标1。确定肺部成熟过程中AEC中Wnt5a信号的功能。具体目标2。确定肺部成熟过程中AMF中Wnt5a信号的功能。特定目的3。确定CaMkII作为下游细胞内介体的作用肺部成熟中的Wnt5a信号传导。健康相关性：肺部成熟是出生后生存的生存要求。如果成功，这项研究的结果可能会对理解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婴儿的疾病。确定WNT5A，RORS和CAMKII在肺部成熟中的作用进一步建议以不同级别的信号转导量的治疗靶标，并且可能允许更具选择性调整此过程。