Role of NFxB/HIF2a axis in renal cell carcinoma progression

NFxB/HIF2a 轴在肾细胞癌进展中的作用

• 批准号: 8566987
• 负责人: E Jason Abel
• 金额: $ 17.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-07 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566987
• 关键词: Accounting; Achievement; Angiogenic Factor; Basic Science; Cancer Center; Cancer Control; Cell Line; Cell Proliferation; Cells; Clinical; Collaborations; Commit; Data; Development; Development Plans; Diagnosis; Disease; Environment; Fellowship; Funding; Future; Genes; Goals; Growth; Growth Factor; Health; Hypervascular; Hypoxia Inducible Factor; In Vitro; Knowledge; Lead; Link; Malignant Epithelial Cell; Malignant Neoplasms; Manuscripts; Mentors; Mentorship; Metastatic Renal Cell Cancer; Modeling; Molecular; Mus; Mutation; Nature; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Outcome; Pathologic; Pathway interactions; Patients; Phenotype; Physicians; Play; Positioning Attribute; Pre-Clinical Model; Probability; Recording of previous events; Regulation; Renal Cell Carcinoma; Renal carcinoma; Research; Research Institute; Research Methodology; Research Personnel; Role; Sampling; Scientist; Signal Transduction; Specimen; Surgeon; Therapeutic; Time; Tissue Microarray; Training; Transcriptional Regulation; Translational Research; Tumor Tissue; United States National Institutes of Health; Universities; Urologic Oncology; Urology; VHL protein; Wisconsin; Work; Xenograft procedure; angiogenesis; base; carcinogenesis; career; career development; design; experience; improved; in vivo; innovation; insight; migration; new technology; novel; novel therapeutic intervention; pre-clinical; programs; promoter; research study; success; therapy development; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

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.

Abel博士是一位积极的年轻科学家和外科医生，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。他过去的成就记录是非凡的，包括11篇关于肾细胞癌（RCC）的手稿。他目前的职位为研究提供了大量受保护的时间，他利用这些时间为这项提案开发了初步数据。他的近期职业目标集中在获得必要的科学知识和经验，成为RCC细胞信号传导领域富有成效的独立调查员。长期的职业目标包括建立一个RCC转化研究计划和开发基于NF-？B信令。Abel博士周围的环境非常适合他发展成为一名独立的调查员。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。宫本茂树博士是一位基础科学家和NF-？B信令谁是致力于阿贝尔博士和他的科学事业发展的密切指导。大卫Jarrard博士是一个成功的医生，科学家，谁将作为一个共同的导师，并与贾森密切合作，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、合作和教学课程，使威斯康星州大学成为世界顶级研究机构之一。据估计，2012年美国将有65，000名患者被诊断患有肾癌。转移性肾细胞癌是一种致死性疾病，治疗很少，大多数患者在诊断后存活不到2年。肾细胞癌是一种高度血管化的肿瘤，产生血管生成和生长因子，由缺氧诱导因子（HIF）的过度表达触发，最近的研究表明，HIF 2？亚基，具体地说，在致癌和进展中起着因果作用。我们的初步研究表明，以前未知的一致激活NF-？B组HIF 2？在RCC临床前模型和临床样品中的表达，表明它们在功能上相关。这个建议的目的是调查的假设，激活NF-？B/HIF 2？轴促进RCC肿瘤生长。在目的1，我们将探讨NF-？B/HIF 2？轴使用在体外实验。鉴于从微环境的重大相互作用的概率，我们设计了目标2，以评估是否NF-？B/HIF 2？轴可能间接促进RCC异种移植瘤的生长。在目标3中，我们将确定与NF-？B激活/HIF 2？表情这项建议是创新的，因为它调查NF-？B/HIF 2？相互作用，这是一个新的途径在RCC。我们的项目是重要的，因为RCC进展是由HIF信号和NF-？B/HIF 2？轴可能允许开发这种不治之症的新疗法。