The cellular basis of CCM gene function in development

发育过程中 CCM 基因功能的细胞基础

• 批准号: 7080202
• 负责人: KEVIN J WHITEHEAD
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080202
• 关键词: angiogenesis; ankyrins; artery; cellular pathology; cerebrovascular disorders; congenital cardiovascular disorder; developmental genetics; developmental neurobiology; gene deletion mutation; genetically modified animals; laboratory mouse; mammalian embryology; microtubule associated protein; protein structure function; transfection /expression vector; vascular endothelium

DESCRIPTION (provided by applicant): This proposal outlines a 5-year plan for the career development of Kevin Whitehead to build upon his research training received as a Pfizer postdoctoral research fellow and to facilitate his transition to independence and excellence in the field of vascular developmental biology. Dean Li, MD, PhD, Associate Professor of Medicine, a recognized leader in the field of vascular developmental biology, will serve as sponsor. Additional scientific and career advice will be obtained from co-sponsor Guy Zimmerman, Professor of Medicine and chair of the program in Human Molecular Biology and Genetics (HMBG) and a recognized expert in vascular cell biology, integrins and selectins. This work will be done in collaboration with Douglas Marchuk, Associate Professor of Genetics at Duke University, and Antonio Duarte, Auxiliary Professor at the Faculty of Veterinary Medicine in Lisbon, Portugal. In addition, a scientific advisory committee will be formed to provide scientific and career advice. Previous work demonstrated an important role in arterial development for Ccm1, a gene responsible for a subset of CCM cases in humans. Proposed research will address the hypothesis that arterial development requires the expression of Ccm1, Ccm2 and Ccm3. Specific aims include: 1) Describe the first developmental role of CCM genes by studying null mutants. 2) Determine the cellular basis for vascular defects, by studying conditional mutants with neural or endothelial mutations of the CCM genes. 3) Describe the cellular basis of CCM gene function by examining the endothelial cell culture phenotype resulting from a lack of CCM gene expression in endothelial cells or adjacent neural cells. The University of Utah provides an ideal environment for the proposed research career award. The University of Utah has excellent core facilities and a rich history of gene targeting in mice. The Division of Cardiology has a strong commitment to developing young academic faculty, and the HMBG program is unique in acting as an interface between basic and clinical science and has provided an ideal environment for the professional development of physician scientists such as Dr. Whitehead.

描述（由申请人提供）： 该提案概述了凯文·怀特海德（Kevin Whitehead）的职业发展计划为期5年，以基于辉瑞博士后研究员的研究培训，并促进他在血管发展生物学领域的独立和卓越的过渡。医学博士Dean Li，医学副教授是血管发育生物学领域的公认领导者，将担任赞助商。其他科学和职业建议将从共同赞助商Guy Zimmerman，医学教授兼人分子生物学和遗传学计划（HMBG）的主席，也是血管细胞生物学，整合蛋白和Selectins的公认专家。这项工作将与杜克大学遗传学副教授的道格拉斯·马尔克克（Douglas Marchuk）和葡萄牙里斯本兽医学院的辅助教授安东尼奥·杜阿尔特（Antonio Duarte）合作。此外，将成立一个科学咨询委员会，以提供科学和职业建议。先前的工作表明，CCM1的动脉发育中起着重要作用，CCM1是一个负责人类CCM病例的基因。拟议的研究将解决以下假设：动脉发展需要CCM1，CCM2和CCM3的表达。具体目的包括：1）通过研究零突变体来描述CCM基因的第一个发展作用。 2）通过研究CCM基因神经或内皮突变的条件突变体来确定血管缺陷的细胞基础。 3）通过检查内皮细胞或相邻神经细胞中CCM基因表达缺乏CCM基因表达而导致的内皮细胞培养表型来描述CCM基因功能的细胞基础。犹他大学为拟议的研究职业奖提供了理想的环境。犹他大学拥有出色的核心设施，并且具有悠久的小鼠基因靶向史。心脏病学部门对发展年轻的学术教师有着坚定的承诺，而HMBG计划在基础科学和临床科学之间的界面方面是独一无二的，并为Whitehead博士等医师科学家的专业发展提供了理想的环境。