Functional and Tissue Specific Effects of VHL Mutations

描述（由申请人提供）： Von HippeI-Lindau（VHL）综合征是以VHL肿瘤抑制基因突变为特征的常染色体显性遗传疾病。 已经观察到基因型-表型相关性，VHL中的特定点突变对应于肿瘤发生的模式。 VHL 1型疾病表现为透明细胞肾细胞癌和小脑血管母细胞瘤。 VHL 2型疾病定义为存在嗜铬细胞瘤，并细分为2A型（嗜铬细胞瘤和血管母细胞瘤）、2B型（嗜铬细胞瘤、肾细胞癌和血管母细胞瘤）和2C型（仅嗜铬细胞瘤）。 VHL突变也发生在大多数散发形式的透明细胞肾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、缺氧反应和血管生成。 VHL在这些过程中的每一个的重要性，因为它们属于肿瘤发生是未知的。 为了解决这个问题，我们提出了以下假设：VHL在细胞内执行多种功能，通过特定的错义突变的个体功能的扰动有助于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代表VHL疾病亚型的一组VHL突变，这一系列实验将区分决定组织特异性肿瘤发生的VHL功能。 该提案描述了一个为期5年的培训计划，以发展癌症生物学的学术生涯。 该提案中描述的实验将在塞莱斯特西蒙博士的指导下为癌症研究提供使用和操作小鼠遗传模型系统的宝贵经验。 Simon博士是霍华德休斯医学研究所的副教授，在动物模型系统的操作方面具有丰富的经验。 此外，Vicki Eng博士的技能已被用于加强小鼠肿瘤模型病理学评估的培训计划。 最后，一个由经验丰富和备受推崇的医学科学家组成的咨询委员会已经成立，提供科学和职业建议。 最终，在这个项目的发展所花费的时间将允许在血管生成和肿瘤发生领域的调查线的建立，并将提供必要的技能，成为一个成功的独立调查。

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.