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热潮，因为几种染色质- 在肿瘤的发生过程中，相关因素已经被确定。一种关键的染色质- 参与活性转录的修饰蛋白SETD2已被发现在 大约15%的肾透明细胞癌(CcRCC)。慢性肾细胞癌患者已经表现出 对化疗和常规放射治疗都有抵抗力，尽管很严重 治疗方面取得了进展，只有一小部分患者表现出持久的临床表现 因此，迫切需要在这一领域采用新的治疗方法。 通常，SETD2突变被归类为功能相同的；然而，它们可以是 根据它们的结构或酶特性分组的。这个项目试图回答 SETD2蛋白的丢失与其酶的丢失在分子上如何区分的问题 活动。第一个目标将使用芯片序列和生化研究来确定两者之间的关系。 SETD2突变与差异性染色质失调的关系及其特异性 另一种蛋白质或多肽片段在缺乏SETD2的情况下发生异常作用的机制。 第二个目标将使用芯片序列和细胞研究来确定不同的分子 CcRCC背景下SETD2突变导致不同ccRCC的机制 发展和进步。 Banaszynski实验室的多学科环境促进了合作 在不同的科学家和受训人员中受益于Banaszynski博士和 绿色生殖生物学中心的知名科学家。在这次培训结束之前 在团契期间，我将实现四个目标，我将：1)成为一名有纪律的实验者，2) 获得我的数据的所有权，3)全面了解基础和当前 塑造癌症生物学领域的文献，以及4)成为有效的科学传播者 和领袖。

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.