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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

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.

摘要