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

项目摘要 近年来，癌症表观遗传学推动了研究的激增，因为几种染色质- 在肿瘤发生的过程中已经确定了相关因素。一种重要的染色质- 参与主动转录的修饰蛋白SETD 2已被发现在转录过程中发生突变。 约15%的透明细胞肾细胞癌（ccRCC）。ccRCC患者显示 对化疗和常规放射治疗的抵抗，尽管主要 虽然已经取得了治疗进展，但只有一小部分患者表现出持久的临床症状， 反应和长期缓解;因此，迫切需要该领域的新疗法。 通常，SETD 2突变被分组为功能上相同的;然而，它们可以是相同的。 根据它们的结构或酶特性进行分组。该项目旨在回答 SETD 2蛋白的丢失如何在分子上不同于其酶的丢失的问题， 活动第一个目标将使用ChIP-seq和生物化学研究来确定 SETD 2突变和差异染色质失调之间的关系，并阐明 另一种蛋白质或肽片段在缺乏SETD 2的情况下异常作用的机制。 第二个目标将使用ChIP-seq和细胞研究来确定不同的分子 在ccRCC的背景下，SETD 2突变的机制导致差异性ccRCC 发展和进步。 Banaszynski实验室的多学科环境促进了合作 在不同的科学家和学员中受益于Banaszynski博士的指导， 绿色生殖生物学中心的科学家。在培训结束时 奖学金期间，我将完成四个目标，我将：1）成为一个有纪律的实验者，2） 获得我的数据的所有权，3）掌握对基础和当前 形成癌症生物学领域的文献，以及4）成为有效的科学传播者 也是领袖

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.