Alveolar Cell Dysfunction and Pulmonary Fibrosis

肺泡细胞功能障碍和肺纤维化

• 批准号: 8054807
• 负责人: Lisa R. Young
• 金额: $ 2.05万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054807
• 关键词: Acute; Adaptor Protein Complex 3; Adaptor Signaling Protein; Adult; Affect; Agonist; Albinism; Alveolar; Alveolar Cell; Alveolar Macrophages; Antibodies; Apoptosis; Automobile Driving; Binding; Biochemical; Biogenesis; Biological; Biology; Bleomycin; Blood Platelets; Bone Marrow Transplantation; Cell Line; Cell physiology; Cells; Childhood; Chronic; Cicatrix; Collagen; Defect; Deposition; Destinations; Dinoprostone; Disease; Epithelial; Epithelial Cells; Exhibits; Exposure to; Fibroblasts; Fibrosis; Functional disorder; Gene Transfer Techniques; Genetic; Goals; Hamman-Rich syndrome; Hermanski-Pudlak Syndrome; Homeostasis; Human; In Vitro; Induction of Apoptosis; Inflammation; Inflammatory; Injury; Interstitial Lung Diseases; Life; Lung; Lung Inflammation; Lung diseases; Macrophage Activation; Marrow; Mediator of activation protein; Medicine; Mentors; Mesenchymal; Molecular; Morbidity - disease rate; Mus; Mutation; Organelles; Pathogenesis; Patients; Pediatrics; Peritoneal Macrophages; Phenotype; Physiology; Platelet Factor 4; Play; Pneumonia; Population; Predisposition; Production; Proteins; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein C; Pulmonology; Regulation; Relative (related person); Research; Research Personnel; Resistance; Role; Stimulus; Stress; Sum; Testing; Therapeutic; Training; Transgenic Mice; Transgenic Organisms; Transplantation; Type II Epithelial Receptor Cell; Wild Type Mouse; Work; abstracting; alveolar homeostasis; alveolar type II cell; autocrine; base; cytokine; defined contribution; design; fibrogenesis; in vivo; insight; instructor; macrophage; monocyte; mortality; mouse model; prevent; programs; promoter; protein transport; response

DESCRIPTION (provided by applicant): The pathogenesis of interstitial lung disease (ILD) is largely unknown, and existing treatments are of limited benefit in alleviating the associated high morbidity and mortality. Abnormalities in alveolar type II cell function are commonly implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and are central features of ILD associated with mutations in surfactant protein C (SP-C) and the ATP-binding cassette A3 (ABCA-3). Monogenic disorders of lung fibrosis provide a unique opportunity to study fibrogenesis from the vantage point of a primary molecular defect. Hermansky-Pudlak Syndrome (HPS) is an autosomal recessive disorder of organellogenesis, characterized by albinism, platelet dysfunction, and highly penetrant and frequently fatal pulmonary fibrosis in the fourth or fifth decade of life. We have found that the naturally occurring Pearl mouse model of HPS, which has a mutation in the adaptor protein 3 (AP-3) complex required for organelle biogenesis and protein trafficking, has a phenotype that mimics the human condition. The Aims of this proposal are: (1) To determine the mechanisms of dysregulated pulmonary inflammation in Pearl HPS mice, and (2) To determine the mechanisms of fibrotic susceptibility in Pearl HPS mice. Both aims will employ genetic and cellular replacement, with type II cell-specific transgenesis and murine bone marrow transplantation, to define the contributions of alveolar macrophages and alveolar type II cells to the pulmonary phenotype of the Pearl mouse. Our long term objective is to use cellular and molecular insights into alveolar homeostasis and the pathogenesis of HPS lung disease to enhance the understanding and therapeutic approach to more common fibrotic lung disorders. The candidate trained in both pediatric and adult pulmonary medicine and is an Instructor of Pediatrics and Medicine. Her research mentor is Dr. Francis X. McCormack. In order to facilitate her goal of becoming an independent basic investigator with an emphasis on mechanisms of pulmonary fibrosis and genetic lung disease, the proposed training plan includes a combination of didactic coursework and mentoring that draws on the expertise in pulmonary biology that exists in Cincinnati. Simply put, this proposal will use a powerful genetic mouse model to understand how scarring occurs in the lung, and how scarring in the lung might be prevented. (End of Abstract)

描述（由申请人提供）： 间质性肺病（ILD）的发病机制在很大程度上是未知的，现有的治疗方法在减轻相关的高发病率和死亡率方面的获益有限。肺泡II型细胞功能异常通常与特发性肺纤维化（IPF）的发病机制有关，是与表面活性蛋白C（SP-C）和ATP结合盒A3（ABCA-3）突变相关的ILD的中心特征。单基因肺纤维化疾病提供了一个独特的机会，研究纤维化的优势，从一个主要的分子缺陷。Hermansky-Pudlak综合征（HPS）是一种常染色体隐性遗传的器官发生疾病，其特征在于白化病、血小板功能障碍以及在生命的第四或第五个十年中高度渗透且经常致命的肺纤维化。我们已经发现，HPS的自然发生的珍珠小鼠模型，其中有一个突变的衔接蛋白3（AP-3）复杂的细胞器生物合成和蛋白质运输所需的，有一个表型，模仿人类的条件。本研究的目的是：（1）明确Pearl HPS小鼠肺部炎症失调的机制;（2）明确Pearl HPS小鼠肺纤维化易感性的机制。这两个目标将采用遗传和细胞替代，与II型细胞特异性转基因和小鼠骨髓移植，以确定肺泡巨噬细胞和肺泡II型细胞的珍珠小鼠的肺表型的贡献。我们的长期目标是利用细胞和分子的见解肺泡稳态和HPS肺病的发病机制，以提高更常见的纤维化肺疾病的理解和治疗方法。候选人接受过儿科和成人肺内科的培训，是儿科和内科的讲师。她的研究导师是弗朗西斯博士。麦科马克为了促进她成为一名独立的基础研究者，重点是肺纤维化和遗传性肺病的机制，拟议的培训计划包括教学课程和指导相结合，借鉴了辛辛那提存在的肺生物学的专业知识。简而言之，这项提议将使用一个强大的遗传小鼠模型来了解肺中疤痕是如何发生的，以及如何预防肺中的疤痕。 (End摘要）