Functional and Tissue Specific Effects of VHL Mutations

描述(申请人提供)：Von Hippei-Lindau(VHL)综合征是一种常染色体显性遗传病，其特征是VHL肿瘤抑制基因突变。已经观察到VHL的特定点突变与肿瘤发生的模式相对应的基因-表型相关性。VHL 1型疾病表现为肾透明细胞癌和小脑血管母细胞瘤。VHL 2型疾病是由嗜铬细胞瘤的存在定义的，并被细分为2A型(嗜铬细胞瘤和血管母细胞瘤)、2B(嗜铬细胞瘤、肾细胞癌和血管母细胞瘤)和2C(仅嗜铬细胞瘤)。VHL的突变也发生在大多数散发性的肾透明细胞癌和血管母细胞瘤中。VHL参与了肿瘤发生的重要细胞过程，包括细胞周期控制、对缺氧的反应和血管生成。VHL在这些过程中的重要性尚不清楚，因为它们与肿瘤的发生有关。为了解决这一问题，我们提出了以下假设：VHL在细胞内发挥多种功能，通过特定的错义突变对个体功能的干扰有助于VHL综合征亚型的肿瘤特异性。通过在组织培养和基因工程动物模型系统中检查一组代表VHL疾病亚型的VHL突变，这一系列实验将区分VHL决定组织特异性肿瘤发生的功能。 这份提案描述了一项为期5年的培训计划，旨在发展癌症生物学的学术生涯。提案中描述的实验将为塞莱斯特·西蒙博士指导下的癌症研究提供使用和操作小鼠遗传模型系统的宝贵经验。西蒙博士是霍华德·休斯医学院的副教授，在动物模型系统的操作方面拥有丰富的经验。此外，Vicki Eng博士的技能已被招募来加强对小鼠肿瘤模型的病理评估的培训计划。最后，一个由经验丰富和备受尊敬的医学科学家组成的咨询委员会已经成立，以提供科学和职业建议。最终，在这个项目开发上花费的时间将允许在血管生成和肿瘤形成领域建立一系列调查，并将提供成为一名成功的独立研究人员所需的技能。

DESCRIPTION (provided by applicant): The Von HippeI-Lindau (VHL) syndrome is an autosomal dominant disorder characterized by mutations in the VHL tumor suppressor gene. Genotype-phenotype correlation has been observed with specific point mutations in VHL corresponding to the patterns of tumorigenesis. VHL type 1 disease displays clear cell renal cell carcinoma and cerebellar hemangioblastoma. VHL type 2 disease is defined by the presence of pheochromocytoma and is subdivided into type 2A (pheochromocytoma and hemangioblastoma), 2B (pheochromocytoma, renal cell cancer, and hemangioblastoma), and 2C (pheochromocytoma only). Mutations in VHL also occur in the majority of sporadic forms of clear cell renal cell carcinoma and hemangioblastoma. VHL has been implicated in cellular processes important for tumorigenesis including cell cycle control, response to oxygen deprivation, and angiogenesis. The importance of VHL in each of these processes as they pertain to tumorigenesis is unknown. To address this we propose the following hypothesis: VHL performs multiple functions within the cell, and perturbation of individual functions via specific missense mutations contributes to the tumor specificity of the VHL syndrome subtypes. By examining a panel of VHL mutations representative of the VHL disease subtypes in both tissue culture and genetically engineered animal model systems, this series of experiments will discriminate functions of VHL which determine tissue specific tumorigenesis. This proposal describes a 5-year training program to develop an academic career in cancer biology. The experiments described in the proposal will provide valuable experience in the use and manipulation of murine genetic model systems for the study of cancer under the mentorship of Dr. Celeste Simon. Dr. Simon is an associate professor in the Howard Hughes Medical Institute with extensive experience in the manipulation of animal model systems. In addition, the skills of Dr. Vicki Eng have been enlisted to enhance the training program in the pathologic evaluation of murine tumor models. Finally, an advisory committee of experienced and highly regarded medical scientists has been assembled to provide scientific and career advice. Ultimately, the time spent in the development of this project will allow the establishment of a line of inquiry in the fields of angiogenesis and tumorigenesis and will provide the skills necessary to become a successful independent investigator.