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Contributions of SETD2 mutations in clear cell renal cell carcinoma (ccRCC)

SETD2 突变在透明细胞肾细胞癌 (ccRCC) 中的作用

基本信息

批准号：
10596500
负责人：
Shilpa Dhar
金额：
$ 3.82万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-16 至 2025-04-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596500
关键词：
Affect Biochemical Biological Assay CRISPR/Cas technology Cancer Biology Cancer Patient Cell Line Cells Cellular Assay Cellular Morphology ChIP-seq Characteristics Chromatin Clear cell renal cell carcinoma Clinical Collaborations Complex DNA Methylation Data Deposition Development Diagnosis Discipline Disease Disease remission Disease-Free Survival Environment Epigenetic Process Fellowship Fostering Functional disorder Genetic Transcription Genomic Instability Genotype Goals Histone-Lysine N-Methyltransferase Histones Intercistronic Region Kidney Neoplasms Laboratories Length Link Literature Location Lysine Malignant Neoplasms Mediating Methyltransferase Missense Mutation Modeling Molecular Mutate Mutation Outcome Ownership Patients Peptide Fragments Pharmacotherapy Physiological Play Precision therapeutics Process Prognosis Protein Fragment Proteins RNA Polymerase II Radiation therapy Renal carcinoma Reproductive Biology Research Resistance Role S-Adenosylhomocysteine S-Adenosylmethionine SET Domain Scientist Shapes System The Cancer Genome Atlas Therapeutic Training Transcript United States amino group cancer subtypes chemotherapy chromatin immunoprecipitation clinically relevant cohort experimental study grasp histone modification improved insight knock-down loss of function methyl group multidisciplinary mutant novel therapeutics patient derived xenograft model protein structure repaired response therapeutic development tumor tumorigenesis wound healing

项目摘要

Project Summary Cancer epigenetics has driven a surge of research in recent years as several chromatin- associated factors have been identified in the process of tumorigenesis. A critical chromatin- modifying protein involved in active transcription, SETD2, has been found to be mutated in approximately 15% of clear cell renal cell carcinomas (ccRCCs). ccRCC patients have shown resistance to both chemotherapy and conventional radiation therapies, and although major therapeutic advances have been made, only a fraction of patients shows durable clinical responses and long-term remission; thus, there is an urgent need for novel therapies in the field. Typically, SETD2 mutations are grouped as functionally identical; however, they can be grouped according to their structural or enzymatic characteristics. This project seeks to answer the question of how the loss of SETD2 protein is molecularly distinct from loss of its enzymatic activities. The first aim will use ChIP-seq and biochemical studies to determine the relationship between SETD2 mutation and differential chromatin dysregulation and to elucidate the particular mechanism in which another protein or peptide fragment acts aberrantly in the absence of SETD2. The second aim will use ChIP-seq and cellular studies to determine how distinct molecular mechanisms of SETD2 mutations in the context of ccRCC results in differential ccRCC development and progression. The multi-disciplinary environment in the Banaszynski laboratory fosters collaboration amongst diverse scientists and trainees benefit from the guidance of Dr. Banaszynski and established scientists in the Green Center for Reproductive Biology. By the end of this training fellowship period, I will accomplish four goals, I will : 1) become a disciplined experimentalist, 2) gain ownership of my data, 3) grasp a thorough understanding of the foundational and current literature that shapes the field of cancer biology, and 4) be an effective scientific communicator and leader.

项目总结