Functional and Tissue Specific Effects of VHL Mutations

描述（由申请人提供）：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。基因型-表型相关性已被观察到与VHL中与肿瘤发生模式相对应的特定点突变。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型疾病的定义是存在嗜铬细胞瘤，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的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与肿瘤发生的重要细胞过程有关，包括细胞周期控制、缺氧反应和血管生成。VHL在这些过程中的重要性，因为它们与肿瘤发生有关，是未知的。为了解决这个问题，我们提出以下假设：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决定组织特异性肿瘤发生的VHL功能。

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.