Regulation of distal lung epithelial regeneration by microRNA-Hippo pathway

microRNA-Hippo通路调控远端肺上皮再生

• 批准号: 9886081
• 负责人: Ying Tian
• 金额: $ 39.35万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886081
• 关键词: Acute; Address; Adult; Affect; Alveolar; Alveolus; Apoptosis; Bacteria; Bacterial Pneumonia; Biological Models; Bleomycin; Cardiac Myocytes; Cell Death; Cell Proliferation; Cells; Chemicals; Child; Development; Distal; Elderly; Embryonic Development; Epithelial; Epithelium; Fibrosis; Gases; Gene Expression; Genes; Genetic Transcription; Heart; Homeostasis; Hyperoxia; Immune response; Inhalation; Injury; Knock-in Mouse; Lung; Lung diseases; Mediating; MicroRNAs; Mus; Natural regeneration; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Pneumococcal Infections; Pneumonia; Population; Process; Proliferating; Publishing; Pulmonary Surfactant-Associated Protein C; Recovery; Regulation; Resistance; Respiratory Tract Infections; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Streptococcus pneumoniae; Structure of parenchyma of lung; Structure of thyroid parafollicular cell; Subgroup; Surface; Testing; Therapeutic; Tissue Differentiation; Transcription Coactivator; Type I Epithelial Receptor Cell; Type II Epithelial Receptor Cell; Virulence; Work; airway epithelium; alveolar epithelium; base; cardiac regeneration; chemotherapy; cyr61 protein; epithelial stem cell; epithelium regeneration; gain of function; improved; injury recovery; irradiation; knock-down; lung injury; lung regeneration; lung repair; mortality; mouse model; novel therapeutic intervention; novel therapeutics; organ growth; overexpression; particle; physiologic model; prevent; public health relevance; regenerative; repaired; response; response to injury; small molecule; stem; stem cells; tissue regeneration; tissue repair

 DESCRIPTION (provided by applicant): The regenerative capacity of airway epithelium in response to injury is critical for lung recovery from environmental insults and preventing the progression of respiratory diseases. So it is important to understand how epithelial regeneration is regulated to potentially enhance recovery and reduce lung injury. MicroRNAs and Hippo pathway have emerged as key modulators of both organ development and adult tissue repair and regeneration. We recently demonstrated that the microRNA cluster, miR302-367, promotes a high level of cell proliferation but less differentiated phenotype in the developing lung and heart. Overexpression of miR302-367 in adult heart promotes cardiomyocyte proliferation and cardiac regeneration. MiR302-367 functions, in part, by targeting several components of the Hippo signaling pathway, which negatively regulates the activity of Yap and Taz. Yap and Taz are key transcriptional co-activators that drive the expression of their downstream targets to promote cell proliferation and inhibit cell death. We have explored the mechanisms that regulate alveolar epithelial repair and regeneration in adult lung following injury induced by bacterial pneumonia. Bacterial pneumonia remains a leading cause of mortality in children and the elderly. While extensive studies have focused on bacterial virulence and host immune responses, little is known about the type lung injury induced by bacterial pneumonia and their subsequent regeneration and repair. We show that mice with infection of Streptococcus pneumoniae (Sp) have markedly injuries in the lung parenchyma followed by visible repair and regeneration. In response to Sp-induced injury, pre-existing SPC-expressing epithelial type II cells in the alveolus function as epithelial progenitor cells. They proliferate and differentiate ito type I cell at the sites of affected alveolar region. Notably, the expression of miR302-367 and Yap/Taz target, Cysteine rich protein 61, is increased in distal lung epithelium. Overexpression of miRNA302-367 in SPC- expressing cells enhanced alveolar epithelial repair and regeneration. Administration of small molecule miR302-mimics in mice with bacterial pneumonia promoted distal airway epithelial regeneration, enhanced mouse recovery and survival. Based on these preliminary studies, we hypothesize that miR302-367 and Hippo pathway regulate lung epithelial gene transcription to promote epithelial repair and regeneration. Targeting microRNA-Hippo pathway may represent a novel therapeutic approach to promote recovery from injury induced by bacterial pneumonia. This project aims to define the mechanistic role of miR302-367 and Hippo signaling in distal airway epithelial repair and regeneration by (1) modulating miR302-367 and Yap/Taz expression in alveolar epithelial progenitor cells in murine model system, and (2) by defining the interactions of miR302-367 and Hippo signaling in governing gene network that control alveolar epithelial repair and regeneration, and (3) by examining the therapeutic potentials of miR-mimics and inhibiting Hippo pathway in recovery from bacteria-induced injury.