权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pro-tumorigenic roles of a VHL isoform in Clear Cell Renal Cell Carcinoma

VHL 亚型在透明细胞肾细胞癌中的促肿瘤作用

基本信息

批准号：
10649049
负责人：
CRISLYN D'SOUZA-SCHOREY
金额：
$ 7.83万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-21 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649049
关键词：
Accounting Affect Behavior Binding Biochemical Biological Cell Line Cell Proliferation Cell Surface Proteins Cell model Cell surface Cells Chromosomal Instability Classification Clear cell renal cell carcinoma Communication Complex Conventional (Clear Cell) Renal Cell Carcinoma Data Development Diagnosis Disease Endothelial Cells Exhibits Exons Genes Germ-Line Mutation Human Hypoxia Inducible Factor Incidence Individual Investigation Knowledge Ligase Lipids Malignant Neoplasms Mediating Membrane Molecular Molecular Abnormality Mutation Neoplasm Metastasis Neoplasms Neoplasms in Vascular Tissue Nucleic Acids Paracrine Communication Pathologic Pathology Patients Phenotype Physiological Pilot Projects Play Population Pre-Clinical Model Protein Isoforms Proteins RNA Splicing Renal Cell Carcinoma Renal carcinoma Research Role Surface Testing Therapeutic Tissues Treatment Protocols Tumor Cell Line Tumor Promotion Tumor Suppressor Proteins United States VHL gene VHL protein Variant Vesicle Von Hippel-Lindau Syndrome Work Xenograft procedure autosome body system cancer cell cancer subtypes cancer type cell type extracellular vesicles gain of function innovation insight intercellular communication mouse model neoplastic cell novel therapeutics protein protein interaction response standard care targeted treatment translational potential tumor tumor microenvironment tumor progression tumorigenesis tumorigenic variant detection young adult

项目摘要

Pro-tumorigenic roles of a VHL isoform in Clear Cell Renal Cell Carcinoma. Kidney cancer or renal cell carcinoma (RCC), is presently the ninth most prevalent neoplasm in the United States. Its incidence has more than doubled in the developed world over the past couple decades and is projected to increase in burden worldwide. The most common subtype of RCC is clear cell RCC (ccRCC), accounting for nearly 80% of all cases. Of note, ccRCCs lack common genetic abnormalities observed in many other human cancers, thus impeding the use of more standard treatment regimens by targeted therapies. Greater than 90% of ccRCC tumors exhibit mutations in the VHL (von Hippel-Lindau) gene. The VHL tumor suppressor gene encodes three different protein isoforms: pVHL213, pVHL160 and pVHL172. pVHL172, an isoform lacking exon 2, is a naturally occurring VHL splice variant, that was recently characterized as lacking tumor suppressor function and having no effect on HIF expression or function unlike the other VHL isoforms, and effectively promoting tumorigenesis in xenograft ccRCC mouse models. Here, to better understand the cellular basis VHL172-driven ccRCC, we propose a set of self-contained studies to investigate paracrine signaling by VHL172 tumor cells. Based on robust preliminary data, we hypothesize that extracellular vesicles (EVs) derived from ccRCC tumors play a key role in the induction of pro-tumorigenic phenotypes. EVs harness select molecular entities—proteins, nucleic acids and lipids, and deliver these cargoes to recipient cells in the tumor microenvironment. We will test our hypothesis and subsequently leverage this work to investigate the role of EVs in preclinical models of ccRCC. These investigations will not only provide new information on EV-mediated intercellular communication in ccRCC, but also new therapeutic avenues to target patients diagnosed with this kidney cancer subtype.

VHL亚型在肾透明细胞癌中的促肿瘤发生作用肾癌或肾细胞癌（RCC），目前是第九个最流行的在美国的肿瘤。其发病率在发达国家增加了一倍多，在过去的几十年里，预计世界范围内的负担将增加。最常见的 RCC的亚型是透明细胞RCC（ccRCC），占所有病例的近80%。值得注意的是， ccRCC缺乏在许多其他人类癌症中观察到的常见遗传异常，因此阻碍靶向治疗使用更标准的治疗方案。大于90% 的ccRCC肿瘤在VHL（von Hippel-Lindau）基因中表现出突变。VHL肿瘤抑制基因编码三种不同的蛋白质同种型：pVHL 213、pVHL 160和pVHL 172。 pVHL 172是一种缺乏外显子2的同种型，是一种天然存在的VHL剪接变体，最近被其特征在于缺乏肿瘤抑制功能并且对HIF表达没有影响，或者功能不同于其他VHL同种型，并有效促进异种移植物中的肿瘤发生 ccRCC小鼠模型。在这里，为了更好地理解细胞基础VHL 172驱动的ccRCC，我们提出了一套独立的研究，以调查VHL 172肿瘤细胞的旁分泌信号。基于强大的初步数据，我们假设细胞外囊泡（EV）来源于 ccRCC肿瘤在诱导促肿瘤发生表型中起关键作用。电动汽车线束选择分子实体-蛋白质，核酸和脂质，并将这些货物运送到肿瘤微环境中的受体细胞。我们将测试我们的假设，利用这项工作来研究EV在ccRCC临床前模型中的作用。这些研究不仅将为EV介导的细胞间通讯提供新的信息，在ccRCC中，也有新的治疗途径，以针对诊断患有这种肾脏的患者癌症亚型