Role of integrin alpha 8 in resolution of lung injury and repair

整合素α8在肺损伤解决和修复中的作用

• 批准号: 9275007
• 负责人: Chi F Hung
• 金额: $ 16.24万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275007
• 关键词: Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Advisory Committees; Affect; Alveolar; Anatomy; Architecture; Biological; Biology; Biomedical Research; Blood Vessels; Body Weight decreased; Cell Communication; Cells; Cellular biology; Cicatrix; Clinical; Collaborations; Complement Factor B; Critical Care; Data; Deposition; Development; Disease; Exhibits; Experimental Models; Extracellular Matrix; Family member; Fibroblasts; Fibrosis; Foundations; Functional disorder; Gases; Genetic Models; Genetic Transcription; Goals; Hamman-Rich syndrome; Human; Hypoxemia; In Vitro; Injury; Integrin alpha Chains; Integrin alphaV; Integrins; Learning; Lung; Lung diseases; Mediating; Medical; Medicine; Mentors; Mesenchymal; Mesenchyme; Mus; Myofibroblast; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Pericytes; Phase; Physicians; Platelet-Derived Growth Factor beta Receptor; Play; Population; Process; Program Development; Pulmonary Fibrosis; Regulation; Research; Research Personnel; Resolution; Role; Scientist; Testing; Training; Training Programs; Transforming Growth Factor beta; Transforming Growth Factors; United States; Work; base; career; career development; experience; fibrogenesis; follow-up; in vivo; indium-bleomycin; interest; killings; lung injury; lung repair; mortality; mouse model; progenitor; programs; public health relevance; repaired

 DESCRIPTION (provided by applicant): Dr. Chi Hung is trained in pulmonary and critical care medicine and has a strong clinical interest in the pathophysiology and management of pulmonary fibrosis and ARDS. His long-term goal is to become an independent physician-scientist focused on lung mesenchymal biology and their role in regulation of lung repair. To achieve this goal, he has developed a comprehensive career development program that builds on his prior training. This includes a research program focused on elucidating the roles of different lung mesenchymal cell populations in regulating lung fibrosis and repair and learning additional mouse models of lung injury. Additionally, Dr. Hung has identified a focused didactic training program, including training in the responsible conduct of biomedical research, co-mentors with complementary strengths and a long track record of collaboration, and a diverse scientific and career advisory committee. The proposed research will focus on the role integrin a8 in lung repair. Preliminary work on integrin a8 suggests it may play a dual role in lung repair: 1) contribute to fibrosis through activation of TGFß in vivo during the repair phase and 2) modulate endothelial repair. While the preliminary data support a role for integrin a8 in lung repair, it is unclear which mesenchymal population is the key effector. To address this question and to test whether different mesenchymal populations utilize integrin a8 to mediate different aspects of lung repair, Dr. Hung will evaluate lung repair through lineage-specific integrin a8 deletion in pericytes and resident fibroblasts in three proposed aims. Specific aim 1 will define the temporal and cellular distribution of integrin a8 over the course of injury. Alterations in integrin a8 expression following injury may provide important clues about its biological activity. In specific aim 2, integrin a8 deletion in the major progenitors of lung myofibroblasts pericytes and resident fibroblasts will address which population is critical for its role in fibrosis, and invitro and in vivo studies will further examine whether its function involves TGFß activation. In specifi aim 3, integrin a8 deletion in pericytes will test whether pericytes utilize integrin a8 in endotheial repair following lung injury.

 描述（由申请人提供）：Chi Hung博士接受过肺部和重症监护医学培训，对肺纤维化和ARDS的病理生理学和管理具有浓厚的临床兴趣。他的长期目标是成为一名独立的医生科学家，专注于肺间充质生物学及其在肺修复调节中的作用。为了实现这一目标，他制定了一个全面的职业发展计划，建立在他以前的培训。这包括一项研究计划，重点是阐明不同肺间充质细胞群在调节肺纤维化和修复中的作用，并学习其他肺损伤小鼠模型。此外，洪博士还确定了一个重点教学培训计划，包括生物医学研究的负责任行为培训，具有互补优势和长期合作记录的共同导师，以及多元化的科学和职业咨询委员会。这项研究的重点是整合素a8在肺修复中的作用。对整合素a8的初步研究表明，它可能在肺修复中发挥双重作用： 1)在修复阶段通过体内TGF β 1的活化促进纤维化和2）调节内皮修复。虽然初步数据支持整合素α 8在肺修复中的作用，但尚不清楚哪种间充质细胞群是关键效应子。为了解决这个问题并测试不同的间充质细胞群是否利用整合素α 8介导肺修复的不同方面，Hung博士将在三个拟议目标中通过周细胞和常驻成纤维细胞中的谱系特异性整合素α 8缺失来评估肺修复。具体目标1将定义整联蛋白a8在损伤过程中的时间和细胞分布。损伤后整合素a8表达的改变可能为其生物学活性提供重要线索。在具体目标2中，肺肌成纤维细胞周细胞和驻留成纤维细胞的主要祖细胞中的整联蛋白α 8缺失将解决哪个群体对其在纤维化中的作用至关重要，并且体外和体内研究将进一步检查其功能是否涉及TGF β活化。在具体的目的3中，周细胞中的整联蛋白a8缺失将测试周细胞是否在肺损伤后的内皮修复中利用整联蛋白a8。