Alveolar Cell Dysfunction and Pulmonary Fibrosis

描述(由申请人提供)： 间质性肺疾病(ILD)的发病机制目前尚不清楚，现有的治疗方法在缓解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，也是与肺表面活性蛋白C(SP-C)和三磷酸腺苷结合盒A3(ABCA-3)突变相关的ILD的主要特征。肺纤维化的单基因紊乱为从原发分子缺陷的角度研究纤维化的发生提供了独特的机会。Hermansky-Pudlak综合征(HPS)是一种常染色体隐性遗传性器官发生疾病，其特征是白化病，血小板功能障碍，以及出生后第四或第五年的高度穿透性和经常致命的肺纤维化。我们发现，自然发生的HPS珍珠小鼠模型在细胞器生物发生和蛋白质运输所需的适配蛋白3(AP-3)复合体中存在突变，其表型模拟人类的情况。本研究的目的是：(1)探讨珍珠HPS小鼠肺部炎症调节失调的机制；(2)探讨珍珠HPS小鼠肺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，以确定肺泡巨噬细胞和II型肺泡细胞对珍珠鼠肺表型的贡献。我们的长期目标是利用对肺泡稳态和HPS肺部疾病发病机制的细胞和分子方面的见解来提高对更常见的纤维性肺部疾病的理解和治疗方法。应聘者接受过儿科和成人肺部医学方面的培训，是儿科和医学的讲师。她的研究导师是弗朗西斯·X·麦科马克博士。为了促进她成为一名独立的基础调查员的目标，重点是肺纤维化和遗传性肺部疾病的机制，拟议的培训计划包括教学课程和辅导相结合，利用辛辛那提现有的肺部生物学专业知识。简单地说，这项提议将使用一个强大的基因小鼠模型来了解肺部疤痕是如何发生的，以及如何防止肺部疤痕形成。 (摘要结束)

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)