Role of NFxB/HIF2a axis in renal cell carcinoma progression

简介(由申请者提供)：亚伯博士是一位积极进取的年轻科学家和外科医生，他致力于成为一名成功的独立研究人员。他在MD Anderson癌症中心完成了泌尿肿瘤学的研究，在那里他获得了基础研究方法和翻译研究方法的经验。他过去的成就是非凡的，包括11篇关于肾癌(RCC)的手稿。他目前的立场为研究留出了大量受保护的时间，他已经利用这些时间为这项提议开发了初步数据。他近期的职业目标是获得必要的科学知识和经验，成为RCC细胞信号领域的一名富有成效的独立研究员。长期的职业目标包括建立肾癌转化研究计划和开发基于核因子-β信号转导的肾癌治疗方法。阿贝尔博士周围的环境非常适合他成长为一名独立的调查员。泌尿科有多名由NIH资助的调查人员的历史，并致力于他的成功。宫本茂树博士是核因子-？B信号方面的基础科学家和世界专家，他致力于亚伯博士及其科学事业发展的密切指导。David Jarrard博士是一位成功的内科科学家，他将担任共同导师，并与Jason密切合作，以促进他在这个竞争激烈的环境中取得成功。Abel博士的职业发展计划利用了培训机会、合作和授课课程，使威斯康星大学成为世界顶尖的研究机构之一。据估计，2012年美国将有6.5万名患者被诊断为肾癌。转移性肾细胞癌是一种致命的疾病，几乎没有治疗方法，大多数患者在确诊后存活不到两年。肾细胞癌是一种高度血管化的肿瘤，通过低氧诱导因子(HIF)的过度表达而产生血管生成和生长因子，最近的研究表明HIF2？具体地说，亚基在癌症的发生和发展中起着因果作用。我们的初步研究证实了一种先前未知的、与HIF2、HIF2、HIF2？在肾癌临床前模型和临床样本中的表达，表明它们在功能上是相关的。本研究的目的是探讨核因子-B/HIF2？AXIS促进RCC肿瘤生长。在目标1中，我们将研究核因子-B/HIF2-1的功能意义。AXIS采用体外实验。考虑到来自微环境的显著相互作用的可能性，我们设计了目标2来评估NF-B/HIF2？Axis可能间接促进肾细胞癌移植瘤的生长。在目标3中，我们将确定与核因子-B活化/HIF2-相关的临床和病理结果。表情。这一建议是创新的，因为它研究了NF-B/HIF2？相互作用，这是肾癌中的一种新途径。我们的项目意义重大，因为肾细胞癌的进展是由HIF信号和对NF-B/HIF2？Axis可能会为这种不治之症开发新的治疗方法。

DESCRIPTION (provided by applicant): Dr. Abel is a motivated young scientist and surgeon who is committed to becoming a successful independent researcher. He completed a fellowship in urologic oncology at the MD Anderson Cancer Center, where he gained experience in basic and translational research methods. His past record of achievement is exceptional, including 11 manuscripts on renal cell carcinoma (RCC). His current position allows significant protected time for research, which he has used to develop preliminary data for this proposal. His immediate career goals focus on gaining the scientific knowledge and experience necessary to become a productive independent investigator in the field of RCC cell signaling. Long term career goals include establishing a RCC translational research program and developing therapies for RCC based on NF-?B signaling. The environment surrounding Dr. Abel is ideal for his development into an independent investigator. The Department of Urology has a history of multiple NIH funded investigators and is committed to his success. Dr. Shigeki Miyamoto is a basic scientist and world expert in NF-?B signaling who is dedicated to the close mentorship of Dr. Abel and his scientific career development. Dr. David Jarrard is a successful physician- scientist, who will serve as a co-mentor and work closely with Jason to facilitate his success in this competitive environment. Dr. Abel's career development plan takes advantage of the training opportunities, collaboration and didactic coursework which make the University of Wisconsin one of the top research institutes in the world. An estimated 65,000 patients in the US will be diagnosed with kidney cancer in 2012. Metastatic RCC is a lethal disease with few treatments, and most patients survive less than 2 years after diagnosis. RCC is a highly vascular tumor, producing angiogenic and growth factors triggered by over-expression of hypoxia inducible factors (HIFs) with recent studies demonstrating that the HIF2? subunit, specifically, plays a causal role in carcinogenesis and progression. Our preliminary studies have demonstrated a previously unknown concordant activation of NF-?B with increased HIF2? expression in RCC preclinical models and clinical samples, suggesting they are functionally related. The purpose of this proposal is to investigate the hypothesis that activation of the NF-?B/HIF2? axis promotes RCC tumor growth. In Aim 1, we will investigate the functional significance of the NF-?B/HIF2? axis using in vitro experiments. Given the probability of significant interaction from the microenvironment, we have designed Aim 2 to evaluate whether the NF-?B/HIF2? axis may indirectly promote tumor growth in RCC xenografts. In Aim 3, we will determine the clinical and pathologic outcomes associated with NF-?B activation/HIF2? expression. This proposal is innovative because it investigates NF-?B/HIF2? interaction, which is a novel pathway in RCC. Our project is significant because RCC progression is driven by HIF signaling and increased understanding of the NF-?B/HIF2? axis may allow development of new therapies for this incurable disease.