Alveolar Cell Dysfunction and Pulmonary Fibrosis

肺泡细胞功能障碍和肺纤维化

• 批准号: 8366897
• 负责人: Lisa R. Young
• 金额: $ 10.77万
• 依托单位: VANDERBILT UNIVERSITY
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366897
• 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; PF4 Gene; Pathogenesis; Patients; Pediatrics; Peritoneal Macrophages; Phenotype; Physiology; 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）： 间质性肺疾病（ILD）的发病机制在很大程度上尚不清楚，现有的治疗方法在减轻相关的高发病率和死亡率方面效果有限。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，并且是与表面活性剂蛋白 C (SP-C) 和 ATP 结合盒 A3 (ABCA-3) 突变相关的 ILD 的核心特征。 ）。肺纤维化的单基因疾病为从原发性分子缺陷的角度研究纤维发生提供了独特的机会。赫曼斯基-普德拉克综合征 (HPS) 是一种常染色体隐性细胞器发生疾病，其特征是白化病、血小板功能障碍，以及在四五十岁时发生高度渗透且常常致命的肺纤维化。我们发现，天然存在的 HPS Pearl 小鼠模型在细胞器生物发生和蛋白质运输所需的衔接蛋白 3 (AP-3) 复合物中存在突变，具有模仿人类状况的表型。该提案的目的是：(1) 确定 Pearl HPS 小鼠肺部炎症失调的机制，(2) 确定 Pearl HPS 小鼠纤维化易感性的机制。这两个目标都将采用遗传和细胞替代，通过 II 型细胞特异性转基因和小鼠骨髓移植，来确定肺泡巨噬细胞和肺泡 II 型细胞对 Pearl 小鼠肺部表型的贡献。我们的长期目标是利用细胞和分子对肺泡稳态和 HPS 肺部疾病发病机制的了解，以增强对更常见的纤维化肺部疾病的理解和治疗方法。该候选人接受过儿科和成人肺医学培训，并且是儿科和医学讲师。她的研究导师是 Francis X. McCormack 博士。为了促进她成为一名独立基础研究者的目标，重点研究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的结合，利用辛辛那提现有的肺生物学专业知识。简而言之，该提案将使用强大的基因小鼠模型来了解肺部疤痕是如何发生的，以及如何预防肺部疤痕。 （摘要完）

项目成果

Neuroendocrine cell hyperplasia of infancy: diagnosis with high-resolution CT.

婴儿期神经内分泌细胞增生：高分辨率 CT 诊断。

• DOI: 10.2214/ajr.09.3385
• 发表时间: 2010
• 期刊: AJR. American journal of roentgenology
• 作者: Brody,AlanS;Guillerman,RPaul;Hay,ThomasC;Wagner,BrandieD;Young,LisaR;Deutsch,GailH;Fan,LelandL;Deterding,RobinR
• 通讯作者: Deterding,RobinR