Identifying a Hypoxia Inducible Factor target profile in Renal Cell Carcinoma tum

鉴定肾细胞癌中缺氧诱导因子的靶标谱

基本信息

批准号：
8535680
负责人：
Alexandra Arreola
金额：
$ 3.45万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535680
关键词：
ARNT gene Affect Alleles Allografting Animal Model Cell Culture System Cell Culture Techniques Cell Line Cell Nucleus Cells Complex Data Environment Epithelial Event Family member Fibrous capsule of kidney Gene Expression Gene Expression Profile Gene Expression Profiling Gene Targeting Genes Germ-Line Mutation Growth Harvest Health Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway Immunocompromised Host Kidney Kidney Neoplasms Link Malignant Neoplasms Methods Missense Mutation Modeling Molecular Mus Mutate Mutation Neonatal Newborn Infant Nude Mice Null Lymphocytes Organism Oxygen Patients Pattern Population Primary Cell Cultures Proteins Public Health Regulation Relative (related person)Renal Cell Carcinoma Renal carcinoma Research Risk Role Stem cells System Teratoma Tissues Transcriptional Activation Transgenic Mice Transportation Tumor Cell Line Tumor Suppressor Genes Ursidae Family VHL mutation Von Hippel-Lindau Syndrome Weight Woman angiogenesis bHLH-PAS factor HLF base capsule cell type disorder subtype glucose metabolism high risk hypoxia inducible factor 1 immunosuppressed insight kidney cell kidney epithelial cell member men mortality mouse model mutant neoplastic cell response tumor tumor growth tumorigenesis tumorigenic ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) is a highly prevalent malignancy with a high mortality rate. Sporadic and germline mutations and/or loss of the von Hippel-Lindau (VHL) tumor suppressor gene have been linked to varying levels of risk for RCC. VHL disease patients have one wild type VHL allele and one inactivated/mutated VHL allele. Tumor formation occurs when the normal copy of VHL is lost or inactivated. Given that VHL 2B missense mutation confers a high risk for RCC, the proposed project aims to identify key molecular changes that occur in renal cells following VHL inactivation that can provide insight into RCC tumor formation. It is well understood that functional pVHL protein under normal oxygen conditions targets hypoxia inducible factors (HIF) for proteosomal degradation, while under low oxygen conditions or mutated VHL allele, VHL fails to regulate HIF-1 subunits. HIF-1 subunits dimerize with HIF-2 subunits, translocate to the nucleus and are responsible for transcriptional activation of genes. Some HIF gene targets have been identified; most notably those important for angiogenesis and glucose metabolism, which are normally upregulated in RCC and other malignant tumors. The focus of this project is to identify a HIF gene target profile by comparing levels of gene expression when HIF-11 and/or HIF-21 are differentially regulated by VHL status using transgenic mouse models. To better understand the genetic changes associated with RCC tumor formation, primary epithelial kidney cells from newborn conditional Vhl null and Vhl 2B transgenic mouse lines will be used and will be harvested and minimally manipulated in an ex vivo system. After which, these cells will be reintroduced to their native environment, renal capsules of immunocompromised mice, to study their tumorigenic potential. The cellular composition of the generated pooled cell lines wilI be identified to investigate which cell type is most at risk for developing tumorigenesis. Whether renal carcinoma is due to VHL disease or sporadic mutations, this study bears great weight to the public, as it is imperative that we understand what changes occur in kidney cells to become tumorigenic. The proposed research will identify the most at-risk cell population and analyze the molecular changes in this at-risk cell population that result in tumor growth as well as identify a HIF gene target profile for these changes in order to have greater insight into RCC tumorigenesis.

描述（由申请人提供）：肾细胞癌（RCC）是一种高度流行的恶性肿瘤，死亡率很高。零星和种系突变和/或von Hippel-Lindau（VHL）抑制肿瘤基因的丧失与RCC风险水平的不同水平有关。 VHL疾病患者有一个野生型VHL等位基因和一个灭活/突变的VHL等位基因。当VHL的正常拷贝丢失或灭活时，就会发生肿瘤形成。鉴于VHL 2B错义突变赋予了RCC的高风险，因此拟议的项目旨在确定VHL失活后肾细胞中发生的关键分子变化，这些变化可以提供对RCC肿瘤形成的见解。众所周知，在正常氧气条件下的功能性PVHL蛋白靶向缺氧诱导因子（HIF）用于蛋白体降解，而在低氧条件或突变的VHL等位基因下，VHL无法调节HIF-1亚基。 HIF-1亚基用HIF-2亚基二聚，转移到核，并负责基因的转录激活。已经确定了一些HIF基因靶标。最值得注意的是，那些对血管生成和葡萄糖代谢很重要的人，通常在RCC和其他恶性肿瘤中上调。该项目的重点是通过比较HIF-11和/或HIF-21的基因表达水平，使用转基因小鼠模型通过VHL状态进行差异调节，来识别HIF基因靶标。为了更好地理解与RCC肿瘤形成相关的遗传变化，将使用来自新生儿条件VHL NULL和VHL 2B转基因小鼠系的原代上皮肾细胞，并将在离体系统中收获并最小化。之后，这些细胞将被重新引入其本地环境，即免疫功能低下的小鼠的肾胶囊，以研究其肿瘤性潜力。确定生成的合并细胞系的细胞组成，以研究哪种细胞类型最有发生肿瘤发生的风险。肾癌是由于VHL疾病还是零星突变引起的，这项研究对公众带来了很大的体重，因为我们必须了解肾细胞中发生的变化以变成肿瘤性。拟议的研究将确定最高危的细胞群体，并分析这种高危细胞种群中的分子变化，从而导致肿瘤生长，并确定这些变化的HIF基因靶标概况，以便更深入地了解RCC肿瘤发生。