Cellular Factors Promoting Renal Cell Carcinoma

促进肾细胞癌的细胞因素

基本信息

批准号：
7560004
负责人：
VINCENT R DAMMAI
金额：
$ 27.74万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7560004
关键词：
Accounting Address Binding Biological Markers Biology Body Fluids CXCR4 gene Cell Culture Techniques Cell Line Cell surface Cells Clear Cell Defect Detection Development Diagnosis Diagnostic Dictyostelium discoideum dynamin A Disease Distant Dynamin Endocytosis Exhibits Extracellular Matrix Failure Fibroblast Growth Factor Receptor 1 Future Goals Growth Human Immigration In Vitro Kidney Kidney Diseases Kidney Neoplasms Knowledge Lead Link Malignant Epithelial Cell Malignant Neoplasms Mass Spectrum Analysis Mediating Membrane Molecular Mus Mutation NME1 gene Neoplasm Metastasis Pathway interactions Peptides Phenotype Process Proliferating Proteins Proteomics Protocols documentation Proximal Kidney Tubules Publishing Regulation Renal Cell Carcinoma Renal carcinoma Research Personnel Role Set protein Signal Transduction Site System TP53 gene Testing Therapeutic Therapeutic Agents Therapeutic Intervention Tissues Toxin Transport Vesicles Tumor Suppressor Genes Two-Dimensional Gel Electrophoresis VHL mutation VHL protein Vascular Endothelial Growth Factors Von Hippel-Lindau Syndrome Xenograft Model base cancer type chemokine receptor clinical application in vivo insight mouse model neoplastic cell novel prevent programs research study small hairpin RNA therapeutic target tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): clear cell Renal Cell Carcinoma (cRCC) account for greater than 90% of Kidney-related malignancies. Our long-term goal is to elucidate cellular factors governing cRCC growth and metastasis as a prerequisite to development of therapeutic intervention protocols capable of alleviating the disease. There are two complimentary objectives of this proposal, namely (i) to elucidate the role of cell surface (CS) and secreted proteins (SP) in kidney tumor growth and metastasis, and (ii) to provide a mechanistic insight into a novel CS and SP accumulation phenotype. The specific aims of the project will test the hypothesis that CS and SP molecules facilitate progression of human cRCC, a kidney cancer type arising from Von Hippel Lindau (VHL) gene mutations. The hypothesis is related to the published study identifying a central role for VHL in dynamin-dependent endocytosis. In further investigating its implications, a novel CS and SP accumulation phenotype was uncovered in VHL -/- cells that is consistent with failure of VHL-mediated dynamin-dependent pathways. The project has four main experimental foci (i) to establish the identity of CS and SP accumulated in cRCC by proteomic analysis, (ii) to provide a mechanistic understanding of the observed CS and SP phenotype, (iii) to study role of the identified CS and SP in cRCC disease process, and (iv) use the knowledge gained for diagnostics and tumor-specific delivery of therapeutic agents. Together these experiments will elucidate cellular mechanisms influencing cRCC biology and their potential applications in diagnosis and treatment. Relevance: The current proposal addresses important aspects of the mechanisms of VHL-related kidney disease that should lead to immediate therapies and future discovery of novel mechanisms of tumorigenesis.

描述（由申请人提供）：透明细胞肾细胞癌 (cRCC) 占肾脏相关恶性肿瘤的 90% 以上。我们的长期目标是阐明控制 cRCC 生长和转移的细胞因素，作为开发能够缓解该疾病的治疗干预方案的先决条件。该提案有两个互补的目标，即（i）阐明细胞表面（CS）和分泌蛋白（SP）在肾肿瘤生长和转移中的作用，以及（ii）提供对新型 CS 和分泌蛋白的机制见解。 SP积累表型。该项目的具体目标将测试 CS 和 SP 分子促进人类 cRCC 进展的假设，cRCC 是一种由 Von Hippel Lindau (VHL) 基因突变引起的肾癌类型。该假设与已发表的研究有关，该研究确定了 VHL 在动力依赖性内吞作用中的核心作用。在进一步研究其含义时，在 VHL -/- 细胞中发现了一种新的 CS 和 SP 积累表型，这与 VHL 介导的动力依赖性途径的失败一致。该项目有四个主要实验重点：(i) 通过蛋白质组分析确定 cRCC 中积累的 CS 和 SP 的身份，(ii) 提供对观察到的 CS 和 SP 表型的机制理解，(iii) 研究已识别的 CS 和 SP 表型的作用cRCC 疾病过程中的 CS 和 SP，以及 (iv) 将获得的知识用于诊断和肿瘤特异性治疗剂的递送。这些实验将共同阐明影响 cRCC 生物学的细胞机制及其在诊断和治疗中的潜在应用。相关性：当前的提案涉及 VHL 相关肾脏疾病机制的重要方面，应导致立即治疗和未来发现肿瘤发生的新机制。