Imapct of Renox on HIF-alpha in Renal Cancer

描述(由申请人提供)： 肾细胞癌(RCC)每年夺走12000名美国人的生命。现有的系统疗法在不到10%的患者中是治愈的，需要有针对性的治疗方法。Von Hippel Lindau(VHL)抑癌基因的缺失是大多数透明细胞肾癌发生发展的早期事件，初步研究表明VHL的一个重要功能是泛素介导的缺氧诱导因子α(HIF-α)降解。缺氧和氧化还原信号通过两种独立的机制调节HIF-α的稳定性和反式激活，这两种机制涉及VHL和转录共激活因子CBP/p300的结合。一种新的肾脏特异的、产生超氧化物的NAD(P)H氧化酶，Renox，最近被描述并被认为是通过分泌促红细胞生成素来维持氧平衡的氧气传感。这种独有的肾功能已知需要HIF转录激活。这一建议的假设是，在没有功能性VHL的情况下，Renox介导的肾细胞内活性氧簇(ROS)的积累会影响HIF-的激活，导致恶性转化。这项工作有三个主要目标。第一个是确定Renox和ROS对HIF-α调节和活性的影响。第二个目的是确定氧化还原信号对HIF-α翻译后修饰的影响。最终目的是特异性地抑制肾素氧合酶功能，以确定其对肾癌发生表型的影响。虽然这项工作与肾癌的发生有很高的相关性，但它在肾脏微环境、疾病状态下的氧化应激和一般肾脏生理领域具有更广泛的影响。候选人是一位在肾癌分子遗传学领域拥有专业知识的泌尿科医生。她最近在国家癌症研究所完成了泌尿外科肿瘤学的研究奖学金。应聘者希望在她75%的时间投入实验室，25%的时间投入教学和临床工作的学术环境中，成为一名独立的内科科学家。这将通过一个全面的计划来实现，该计划将在两位杰出的导师Shuk Mei Ho和Gary Stein的指导下获得技术和智力技能，并利用加州大学马萨诸塞医学院社区内许多研究人员的科学优势。这将为完成这一项目提供一个良好的环境，并为过渡到独立调查员奠定基础。

DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) takes 12,000 American lives each year. Existing systemic therapies are curative in fewer than 10% of patients, and targeted therapeutic approaches are needed. Loss of the von Hippel Lindau (VHL) tumor suppressor is an early event in the development of most clear cell RCC, and preliminary studies have indicated that a critical function of VHL is ubiquitin-mediated degradation of hypoxia inducible factor alpha (HIF-alpha). HIF-alpha stability and transactivation are regulated by hypoxia and redox signaling by two independent mechanisms that involve binding of VHL and the transcriptional co-activator CBP/p300. A novel kidney-specific, superoxide-producing NAD(P)H oxidase, Renox, was recently described and implicated in oxygen sensing for maintenance of oxygen homeostasis via secretion of erythropoeitin. This exclusive renal function is known to require HIF transcriptional activation. The hypothesis of this proposal is that Renox-mediated accumulation of reactive oxygen species (ROS) within the renal cell influences activation of HIF-( leading to malignant transformation in the absence of functional VHL. There are three major aims of this work. The first is to determine the effect of Renox and ROS upon HIF-alpha regulation and activity. A second aim is to determine the effect of redox signaling upon HIF-alpha post-translational modification. The final aim is to specifically inhibit Renox function to determine its effects on the tumorigenic phenotype of renal cell carcinoma. Although this work is of high relevance to renal carcinogenesis, its has broader implications in the areas of renal microenvironment, oxidative stress in disease states, and general renal physiology. The candidate is a urologist with expertise in the area of molecular genetics of kidney cancer. She recently completed a research fellowship in urologic oncology at the National Cancer Institute. The candidate seeks to establish a career as an independent physician-scientist in an academic setting where 75% of her time is devoted to the laboratory and 25% to teaching and.clinical work. This will be achieved by a comprehensive program to acquire both technical and intellectual skills under the guidance of two distinguished and outstanding mentors, Shuk Mei Ho and Gary Stein, and to draw upon the scientific strengths of a number of investigators within the UMass Medical School community. This will provide an excellent environment for completion of this project and a basis for transition to independent investigator.