Gli1 in murine lung development and differentiation

描述（由申请人提供）： 博士安东尼·格伯是一名肺病和重症监护医生，对发育生物学有明确的兴趣，他是华盛顿大学医学科学家培训计划的一员。 他的总体职业目标是通过在学术医学中心研究发育途径和肺部疾病之间的关系，将他的临床和基础科学兴趣联合收割机结合起来。 本提案旨在提供实现这一目标的框架。 通过一系列具体的目标，Gerber博士将测试关于刺猬（Hh）通路（一个关键的发育控制网络）在肺中的作用的几个假设。 具体来说，他将探讨转基因的Hh调节转录因子，Gli 1，在肺上皮和间充质的错误表达的影响。 这将测试假设，即Gli 1调节发育中的肺的模式，增殖和分化。 Hh信号在肺中的作用随时间变化的假设将使用Gli 1错误表达的时间调节进行测试。 微阵列还将用于识别肺中Hh信号的靶点，以测试不同基因子集在不同时间对Hh信号作出反应的假设;最终将使用小鼠和细胞培养模型评估Gli 1对基因激活和肺损伤的影响。 所提出的工作与肺部疾病的相关性是基于发育途径在疾病中被激活的一般概念，以及最近的具体观察结果，即Hh途径在肺损伤时被激活，并在肺癌和肺纤维化中表达。 此外，该提案旨在补充Gerber博士先前的实验室经验，并为他提供肺发育方面的必要技术和知识背景，以作为独立研究者。 一个由医生和科学家组成的委员会将监督格伯博士的独立发展;他的科学发展也将通过参加加州大学旧金山分校的几个系列研讨会、部门务虚会和全国会议来丰富。 UCSF致力于学术医学事业的发展，在资助期结束时，Gerber博士将准备开始作为独立医生科学家的职业生涯，调查在肺部疾病中活跃的发展途径。

DESCRIPTION (provided by applicant): Dr. Anthony Gerber is a pulmonary and critical care physician with a well-defined interest in developmental biology that was fostered as a member of the medical scientist training program at the University of Washington. His overall career objective is to combine his clinical and basic science interests through studying the relationship between developmental pathways and lung disease in an academic medical center. This proposal is constructed to provide the framework to achieve that goal. Through a series of specific aims, Dr. Gerber will test several hypotheses regarding the role of the hedgehog (Hh) pathway, a critical developmental control network, in the lung. Specifically, he will explore the effects of transgenic misexpression of the Hh regulated transcription factor, Gli1, in the lung epithelium and mesenchyme. This will test the hyopthesis that Gli1 regulates patterning, proliferation, and differentiation in the developing lung. The hypothesis that the effects of Hh signaling in the lung vary depending on timing will be tested using temporal regulation of Gli1 mis-expression. Microarrays will also be used to identify targets of Hh signaling in the lung to test the hyopthesis that distinct subsets of genes respond to the Hh signal at different times; ultimately the effects of Gli1 on gene activation and lung injury will be assessed using mouse and cell culture models. The relevance of the proposed work to lung disease is based on the general notion that developmental pathways are activated in disease, coupled with specific recent observations that the Hh pathway is activated in response to lung injury and is expressed in lung cancer and pulmonary fibrosis. Additionally, this proposal is designed to complement Dr. Gerber's prior laboratory experience and provide him with the requisite technical and intellectual background in lung development to function as an independent investigator. A committee of physicians and scientists will oversee Dr. Gerber's progression towards independence; his scientific development will also be enriched through attendance at several seminar series at UCSF, departmental retreats, and national meetings. UCSF is committed to the development of careers in academic medicine, and at the end of the grant period, Dr. Gerber will be prepared to embark on a career as an independent physician scientist investigating developmental pathways that are active in lung disease.