Role of fumarate hydratase in renal hypoxia and tumorigenesis

富马酸水合酶在肾缺氧和肿瘤发生中的作用

基本信息

批准号：
8546186
负责人：
SUNIL SUDARSHAN
金额：
$ 17.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-28 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8546186
关键词：
Accounting Affect Age Antioxidants Biochemical Biological Models Cancer Biology Cell Hypoxia Cell model Citric Acid Cycle Clinical Code Complex Cutaneous Leiomyoma Cytoplasm Data Development Enzymes Fibroid Tumor Fumarate Hydratase Fumarates General Population Generations Genes Germ-Line Mutation Goals Hereditary Leiomyomatosis and Renal Cell Cancer Hereditary Neoplastic Syndromes Hydration status Hypoxia Hypoxia Inducible Factor In Vitro Individual Inherited Intervention Kidney Laboratories Link Malates Malignant - descriptor Malignant Neoplasms Mediating Mentors Metabolism Mitochondria Modeling Molecular Molecular Profiling Mutation NADPH Oxidase Oncogenic Operative Surgical Procedures Oxidation-Reduction Oxidative Stress Pathogenesis Pathway interactions Patients Phenotype Physicians Physiology Post-Translational Protein Processing Process Procollagen-Proline Dioxygenase Proteins Reactive Oxygen Species Renal Cell Carcinoma Renal carcinoma Reporting Research Risk Role Scientist Signal Transduction Syndrome System Systemic Therapy Testing Therapeutic Translating Tumor Suppressor Genes United States Up-Regulation Uterine Fibroids Uterus Variant Vascular Endothelial Growth Factors Woman angiogenesis cancer cell cell growth gene replacement hypoxia inducible factor 1 in vivo insight mitochondrial dysfunction neoplastic cell novel therapeutics protein expression public health relevance renal hypoxia response transcription factor tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a recently identified hereditary form of kidney cancer linked to germline mutations of the FH gene which encodes the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase. HLRCC kidney cancers are remarkable for their biologic aggressiveness. Unfortunately, effective systemic therapies are lacking for patients with advanced kidney cancer. Affected individuals are also at risk for leiomyomas of the skin and uterus. In addition, intervention for women affected by HLRCC fibroids often requires surgical intervention at an early age. Interestingly, FH mutations have also been identified in a subset of sporadic uterine leiomyomas. HLRCC tumor formation may result from the biochemical consequences of loss of FH activity. In particular, aberrant stabilization of the transcription factor hypoxia inducible factor (HIF), a phenomenon referred to as pseudohypoxia, may result in tumor formation via upregulation of potentially carcinogenic genes. Pseudohypoxia has also been implicated in the pathogenesis of several other tumors including the most common variant of kidney cancer. Preliminary data from our laboratory indicates that loss of FH activity is associated with heightened cellular levels of reactive oxygen species (ROS). As such, we hypothesize that ROS drives pseudohypoxia in HLRCC. In order to test this hypothesis, a five-year mentored research plan is outlined under the guidance of experts in cancer biology and renal redox physiology. This plan will enable the candidate to become an independent physician-scientist whose goal is to further understanding of renal cell carcinoma through the study of inherited forms of kidney cancer. The long term objective will be to translate these findings into effective clinical therapeutics. First, the basic mechanisms by which loss of FH leads to elevated cellular ROS will be determined. Secondly, the contribution of reactive oxygen species to pseudohypoxia in FH null tumors will be assessed by examining the effects of ROS on post-translational modifications of HIF-11 in this system. Third, the biologic significance of our findings will be determined in an orthotopic tumor model of HLRCC. These studies will be achieved through a combination of gene replacement and gene knockdown cellular models of HLRCC. Overall, this proposal will utilize HLRCC as model system to identify new therapeutic strategies for patients with cancers that may be driven by ROS-mediated HIF stabilization. PUBLIC HEALTH RELEVANCE: Kidney cancer is an increasingly common malignancy in the United States. This proposal aims to utilize a hereditary form of kidney cancer, referred to as Hereditary Leiomyomatosis and Renal Cell Cancer, to provide insight into more common variants of kidney cancer in the general population. Elucidation of the molecular pathways of this particular variant may help develop novel therapeutic strategies for individuals with cancer.

描述（由申请人提供）：遗传性平滑肌瘤病和肾细胞癌（HLRCC）是最近确定的肾脏癌的遗传形式，与FH基因的生殖线突变有关，该基因编码了三羧酸（TCA）循环酶富马酸水酸盐酶。 HLRCC肾脏癌的生物学侵略性很大。不幸的是，晚期肾癌患者缺乏有效的全身疗法。受影响的个体也有皮肤和子宫平滑肌瘤的风险。此外，对受HLRCC肌瘤影响的妇女的干预通常需要在很小的时候就需要手术干预。有趣的是，在零星子宫平滑肌瘤的一部分中也发现了FH突变。 HLRCC肿瘤的形成可能是由于FH活性丧失的生化后果。特别是，转录因子缺氧诱导因子（HIF）的异常稳定是一种称为伪粘氧化的现象，可能通过上调潜在的致癌基因而导致肿瘤形成。假氧气还与其他几种肿瘤的发病机理有关，包括最常见的肾癌变异。来自我们实验室的初步数据表明，FH活性的丧失与活性氧（ROS）的细胞水平升高有关。因此，我们假设ROS在HLRCC中驱动假氧化。为了检验这一假设，在癌症生物学和肾脏氧化还原生理学专家的指导下概述了一项为期五年的指导研究计划。该计划将使候选人能够成为独立的医师科学家，其目标是通过研究遗传形式的肾癌形式进一步了解肾细胞癌。长期目标是将这些发现转化为有效的临床治疗剂。首先，将确定FH丢失导致细胞ROS升高的基本机制。其次，将通过检查ROS对该系统中HIF-11的翻译后修饰的影响来评估活性氧对FH无效肿瘤中假氧气的贡献。第三，我们的发现的生物学意义将在HLRCC的原位肿瘤模型中确定。这些研究将通过HLRCC的基因替代和基因敲低细胞模型的结合来实现。总体而言，该建议将利用HLRCC作为模型系统来确定可能由ROS介导的HIF稳定驱动的癌症患者的新治疗策略。公共卫生相关性：肾癌在美国越来越普遍。该提案旨在利用遗传形式的肾癌（称为遗传性平滑肌瘤病和肾细胞癌），以洞悉普通群体中肾癌更常见的变体。阐明这种特定变体的分子途径可能有助于为癌症患者开发新的治疗策略。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Another small molecule in the oncometabolite mix: L-2-Hydroxyglutarate in kidney cancer.

致癌代谢物混合物中的另一种小分子：肾癌中的 L-2-羟基戊二酸。

DOI：
10.18632/oncoscience.165
发表时间：
2015
期刊：
Oncoscience
影响因子：
0
作者：
Shim,Eun-Hee;Sudarshan,Sunil
通讯作者：
Sudarshan,Sunil

Point mutations of the mTOR-RHEB pathway in renal cell carcinoma.

DOI：
10.18632/oncotarget.4963
发表时间：
2015-07-20
期刊：
Oncotarget
影响因子：
0
作者：
Ghosh AP;Marshall CB;Coric T;Shim EH;Kirkman R;Ballestas ME;Ikura M;Bjornsti MA;Sudarshan S
通讯作者：
Sudarshan S