Role of NFxB/HIF2a axis in renal cell carcinoma progression

Abel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安德森癌症中心完成了泌尿肿瘤学的研究，在那里他获得了基础和转化研究方法的经验。他过去的成就是非凡的，包括11篇关于肾细胞癌（RCC）的论文。他目前的职位为研究提供了大量受保护的时间，他利用这些时间为本提案开发了初步数据。他近期的职业目标是获得必要的科学知识和经验，成为RCC细胞信号领域富有成效的独立研究者。长期职业目标包括建立RCC转化研究项目和开发基于NFκB信号的RCC治疗方法。阿贝尔博士所处的环境非常适合他成长为一名独立调查员。泌尿科有多个NIH资助的研究人员的历史，并致力于他的成功。Shigeki Miyamoto博士是一位基础科学家和NF-κB信号的世界专家，他致力于Abel博士的密切指导和他的科学事业发展。David Jarrard博士是一位成功的内科科学家，他将作为Jason的共同导师并与Jason密切合作，以促进他在这个竞争激烈的环境中取得成功。阿贝尔博士的职业发展计划充分利用了威斯康星大学作为世界顶尖研究机构之一的培训机会、合作和教学课程。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很少治疗的致命疾病，大多数患者在诊断后存活不到2年。RCC是一种高度血管性肿瘤，由缺氧诱导因子（hypoxia inducible factors, hfs）的过度表达引发血管生成因子和生长因子，最近的研究表明，特别是HIF2α亚基在癌的发生和进展中起着因果作用。我们的初步研究表明，在RCC临床前模型和临床样本中，NF-κB的激活与HIF2α表达的增加是一致的，这表明它们在功能上是相关的。本研究的目的是探讨NF-κB/HIF2α轴的激活促进RCC肿瘤生长的假设。在Aim 1中，我们将通过体外实验研究NF-κB/HIF2α轴的功能意义。考虑到微环境显著相互作用的可能性，我们设计了Aim 2来评估NF-κB/HIF2α轴是否可能间接促进RCC异种移植物的肿瘤生长。在Aim 3中，我们将确定与NF-κB活化/HIF2α表达相关的临床和病理结果。这一建议具有创新性，因为它研究了NF-κB/HIF2α相互作用，这是RCC的一个新途径。我们的项目意义重大，因为RCC的进展是由HIF信号驱动的，对NF-κB/HIF2α轴的进一步了解可能有助于开发这种不治之症的新疗法。

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 NFκB 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-κB 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 HIF2α subunit, specifically, plays a causal role in carcinogenesis and progression. Our preliminary studies have demonstrated a previously unknown concordant activation of NF-κB with increased HIF2α 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-κB/HIF2α axis promotes RCC tumor growth. In Aim 1, we will investigate the functional significance of the NF-κB/HIF2α axis using in vitro experiments. Given the probability of significant interaction from the microenvironment, we have designed Aim 2 to evaluate whether the NF-κB/HIF2α axis may indirectly promote tumor growth in RCC xenografts. In Aim 3, we will determine the clinical and pathologic outcomes associated with NF-κB activation/HIF2α expression. This proposal is innovative because it investigates NF-κB/HIF2α 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-κB/HIF2α axis may allow development of new therapies for this incurable disease.