Impact of Renox on HIF-alpha in Renal Cancer

Renox 对肾癌 HIF-α 的影响

• 批准号: 6675234
• 负责人: JODI Kathleen MARANCHIE
• 金额: $ 12.91万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6675234
• 关键词: NAD(P)H dehydrogenase; aerobiosis; angiogenesis; biological signal transduction; enzyme activity; free radical oxygen; hypoxia inducible factor 1; kidney cell; kidney neoplasms; laboratory mouse; oxidative stress; posttranslational modifications; protein structure function; tissue /cell culture; tumor suppressor genes

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.

描述（由申请人提供）： 肾细胞癌（RCC）每年享受12,000名美国人的生命。现有的全身疗法在不到10％的患者中是治愈性的，需要采用靶向治疗方法。 von Hippel-Lindau（VHL）肿瘤抑制剂的丧失是最清晰的细胞RCC发展的早期事件，初步研究表明，VHL的关键功能是泛素介导的低氧诱导因子Alpha（HIF-Alpha）的降解降解。 HIF-Alpha稳定性和反式激活受到缺氧和氧化还原信号的调节，这两种独立的机制涉及VHL的结合和转录共激活器CBP/P300。最近描述并与氧气相关的一种新型肾脏特异性的，超氧化物的NAD（P）H氧化酶Renox，与氧气相关，以维持氧气稳态，这是通过分泌红细胞素的。已知该独家肾功能需要HIF转录激活。该建议的假设是，肾脏介导的活性氧（ROS）在肾细胞内影响HIF-的激活（导致在缺乏功能性VHL的情况下导致恶性转化。这项工作的三个主要目的。第一个是确定Renox和Ros对Hif-Alpha调节的影响。翻译后的修改是最终的目标是抑制肾脏的作用，以确定肾细胞癌的肿瘤表型。她最近在国家癌症研究所完成了泌尿科肿瘤学研究金。这将通过一项综合计划来实现，以在两位杰出和杰出的导师Shuk Mei Ho和Gary Stein的指导下同时获得技术和智力技能，并借鉴UMass医学院社区中许多研究人员的科学优势。这将为完成该项目的完成和过渡到独立调查员的基础提供一个绝佳的环境。