Gli1 in murine lung development and differentiation

Gli1 在小鼠肺发育和分化中的作用

• 批准号: 6956616
• 负责人: ANTHONY N GERBER
• 金额: $ 12.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956616
• 关键词: biological models; biological signal transduction; cell differentiation; cell growth regulation; cell proliferation; developmental genetics; gene expression; genetically modified animals; in situ hybridization; laboratory mouse; lung development; lung injury; mesenchyme; microarray technology; protein structure function; respiratory epithelium; tissue /cell culture; transcription factor

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.

描述（由申请人提供）： 安东尼·格伯 (Anthony Gerber) 博士是一名肺科和重症监护医师，对发育生物学有着明确的兴趣，这种兴趣是作为华盛顿大学医学科学家培训项目的成员培养起来的。 他的总体职业目标是通过在学术医学中心研究发育途径与肺部疾病之间的关系，将他的临床和基础科学兴趣结合起来。 该提案旨在提供实现该目标的框架。 通过一系列具体目标，格伯博士将测试有关刺猬 (Hh) 通路（肺部重要的发育控制网络）作用的几个假设。 具体来说，他将探索 Hh 调节转录因子 Gli1 的转基因错误表达对肺上皮和间质的影响。 这将检验 Gli1 调节发育中肺部的模式、增殖和分化的假设。 肺中 Hh 信号传导的影响随时间而变化的假设将使用 Gli1 错误表达的时间调节进行测试。 微阵列还将用于识别肺部 Hh 信号传导的靶标，以测试不同基因子集在不同时间对 Hh 信号做出反应的假设；最终，Gli1 对基因激活和肺损伤的影响将使用小鼠和细胞培养模型进行评估。 拟议工作与肺部疾病的相关性基于以下一般概念：发育途径在疾病中被激活，再加上最近的具体观察结果，即 Hh 途径因肺损伤而被激活，并在肺癌和肺纤维化中表达。 此外，该提案旨在补充 Gerber 博士之前的实验室经验，并为他提供作为独立研究者所需的肺部发育技术和知识背景。 一个由医生和科学家组成的委员会将监督格伯博士走向独立的进展；通过参加加州大学旧金山分校的多个系列研讨会、部门务虚会和全国会议，他的科学发展也将得到丰富。 加州大学旧金山分校致力于学术医学职业的发展，在资助期结束时，格伯博士将准备开始作为一名独立医师科学家的职业生涯，研究肺部疾病的活跃发展途径。