Alveolization in Fibrillin-1 Defective Mice

描述(由申请人提供)： 气体交换受损的疾病，如肺气肿和肺纤维化， 流行的，临床负担重，难以治疗的。因为肺 移植仍然是治疗这些疾病的唯一确定的选择。 对于疾病，人们的兴趣主要集中在了解细胞和 肺泡形成的分子基础。因为目前对哺乳动物的认识 肺泡成形术是相当有限的，这笔赠款是针对探索 小鼠肺泡间隔受损机制的研究 了解正常隔膜的要求。PI最近观察到 两个品系的纤维蛋白I缺陷小鼠的远端空隙扩大 已发现转化生长因子-β是这一缺陷的关键介体。第一 目的是确定3例鼻中隔受损的自然病史。 纤维蛋白-1缺陷小鼠模型。这一追求应该确定是否 间隔缺陷可能是导致先天性心脏病发生的重要危险因素 肺气肿和肺纤维化。肺泡化的自然历史 这些模型中的缺陷将与异常转化生长因子-β的进化相关。 之前在其中两个模型中观察到的信号。第二个目标 就是找出肺形态异常出现在 观察到的间隔缺陷，以努力揭示关键的介体 分隔符。将使用几种方法来确定是否 肺血管发育异常、基质成分异常或两者兼而有之 这是隔膜破裂的基础。最终目标是使用 基于芯片技术的小鼠肺组织基因表达谱研究 隔膜的重要介体。这个项目的PI是一名 医学部。她致力于学术医学的事业。 她计划将80%的时间花在研究上。她已经有了 以前接受过信号转导方面的培训，最近则使用了 用于探测人类疾病的转基因小鼠模型。她现在想扩大她的业务范围 研究兴趣：研究哺乳动物的肺发育。要实现 这一次，她将参加关于小鼠发育的赞助课程并参加 约翰斯·霍普金斯大学发展遗传学系讲座 医学。约翰霍普金斯大学的环境提供了几个受人尊敬的 能够指导使用小鼠模型探测肺的科学家 病理学和发育异常。他们的参与以及 在肺内科和肺科的正规教育计划 基因医学研究所应促进她所述的成就 研究目标以及帮助她发展成为完全独立的 调查员。

DESCRIPTION (provided by applicant): Diseases of impaired gas exchange, such as emphysema and lung fibrosis, are prevalent, clinically burdensome ,and difficult to treat. Because lung transplantation remains the only definitive treatment option for these diseases, much interest has been focused upon understanding the cellular and molecular basis of alveolar formation. As the current knowledge of mammalian lung alveolization is quite limited, this grant is directed towards exploring the mechanism of impaired alveolar septation in mouse models in an effort to understand the requirements of normal septation. The PI has recently observed distal airspace enlargement in two strains of fibrillin-I deficient mice and has found that TGF-beta is a critical mediator of this defect. The first objective is to determine the natural history of impaired septation in three fibrillin-1 defective mouse models. This pursuit should establish whether septation defects may represent important risk factors for the development of emphysema and pulmonary fibrosis. The natural history of the alveolization defects in these models will be correlated with the evolution of aberrant TGF-beta signaling previously observed in two of the models. The second objective is to identify the pulmonary morphologic aberrations which precede the observed septation defects in an effort to reveal critical mediators of septation. Several approaches will be employed to establish whether abnormalities in pulmonary vascular development, matrix composition, or both underlie the disruptions in septation. The final objective is to use chip-based gene expression profiling of murine lung to identify novel and important mediators of septation. The PI of this project is an instructor in the Department of Medicine. She is committed to a career in academic medicine and plans to spend 80 percent of her time in research pursuits. She has had previous training in signal transduction and, more recently, the use of transgenic mouse models to probe human disease. She now wants to expand her research interests to investigating mammalian lung development. To achieve this, she will take sponsored courses on murine development and attend lectures in the developmental genetics department at Johns Hopkins School of Medicine. The environment at Johns Hopkins provides several esteemed scientists who can provide guidance in the use of mouse models to probe lung pathology and developmental aberrations. Their involvement as well as a formal education program in both the Division of Pulmonary Medicine and Institute of Genetic Medicine should facilitate the achievement of her stated research objectives as well as aid in her development into a fully independent investigator.