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) 每年夺去 12,000 名美国人的生命。现有的全身疗法对不到 10% 的患者有疗效，因此需要有针对性的治疗方法。 von Hippel Lindau (VHL) 肿瘤抑制因子的缺失是大多数透明细胞肾细胞癌发展的早期事件，初步研究表明 VHL 的一个关键功能是泛素介导的缺氧诱导因子 α (HIF-α) 的降解。 HIF-α 稳定性和反式激活受缺氧和氧化还原信号传导的调节，这两种独立机制涉及 VHL 和转录共激活剂 CBP/p300 的结合。最近描述了一种新型肾脏特异性、产生超氧化物的 NAD(P)H 氧化酶 Renox，并涉及通过分泌促红细胞生成素维持氧稳态的氧传感。已知这种独特的肾功能需要 HIF 转录激活。该提议的假设是，Renox 介导的肾细胞内活性氧 (ROS) 的积累会影响 HIF-( 的激活，从而在缺乏功能性 VHL 的情况下导致恶性转化。这项工作有三个主要目标。第一个目的是确定 Renox 和 ROS 对 HIF-α 调节和活性的影响。第二个目标是确定氧化还原信号对 HIF-α 翻译后修饰的影响，最终目标是特异性抑制 Renox 功能以确定其影响。关于致瘤性尽管这项工作与肾癌发生高度相关，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学领域具有更广泛的影响。她最近在国家癌症研究所完成了泌尿肿瘤学的研究奖学金，该候选人寻求在学术环境中建立自己的职业生涯，其中 75% 的时间都投入其中。到实验室，25% 到教学和临床工作。这将通过在两位杰出导师 Shuk Mei Ho 和 Gary Stein 的指导下获得技术和智力技能的综合计划来实现，并利用麻省大学医学院社区内许多研究人员的科学优势。这将为完成该项目提供良好的环境，并为过渡到独立研究者奠定基础。