Investigating the function of MTBP in lymphoma

描述(申请人提供)：癌细胞依赖于癌基因诱导的、过度增殖的信号来生长和存活。C-Myc，一种调节细胞的转录因子 周期进展，即细胞的生长和增殖，是人类癌症中最常见的过度表达的癌基因之一。MYC在70%的人类恶性肿瘤中过度表达，包括非霍奇金淋巴瘤，美国每年约有2万人死于非霍奇金淋巴瘤。尽管对Myc的功能和活性进行了数十年的研究，但仍有许多问题尚未解决，到目前为止还没有针对Myc的成功治疗方法。最近，有人提出，间接靶向Myc可能有助于克服缺乏治疗Myc驱动的癌症的成功疗法。然而，Myc的调节是高度复杂的，许多调节Myc活性的蛋白质的特性和功能仍然未知或描述得很差。因此，鉴定和评价与Myc相互作用的蛋白质并调节其功能是至关重要的。我们有初步数据表明，MTBP是一种蛋白质，我们之前已经证明与Myc驱动的增殖和淋巴肿大有关，它与Myc结合在一个复合体中，并调节其致癌功能。因此，我们假设MTBP是Myc的一种新的转录调节因子，在淋巴瘤的发生和生存中起着关键作用。为了验证这一假设，我们提出了两个利用体内和体外模型系统的具体目标。在目标1中，我们将利用分子和生化手段来阐明MTBP调节Myc转录活性的机制。在目标2中，我们将使用在体小鼠模型系统来评估MTBP的致癌活性，并表征其在淋巴瘤发生和生存中的作用。我们还将利用人类淋巴瘤细胞系将我们的发现与小鼠和人类联系起来，并提供临床意义。我们的结果将显著增强我们对Myc是如何调控的理解，并将表征一种新的调控Myc的蛋白质的功能。我们预计，我们的发现将确定治疗Myc驱动的恶性肿瘤的新靶点。范德比尔特大学医学院医学博士/博士项目的学生所接受的具有挑战性的全面培训将使我能够实现这项建议的目标，并将为我提供成为一名成功的、独立的内科科学家所必需的教育。在整个培训过程中，我将学会批判性思维，评估数据，提出新的假设，并在实验室成功回答科学问题。这将通过研讨会、期刊俱乐部、教学课程、科学会议、文献分析以及与我的导师、论文委员会和其他科学家进行深思熟虑的讨论来实现。这份提案中概述的教育和职业发展目标将帮助我实现成为癌症研究领域一名成功的、独立的内科科学家的目标。

DESCRIPTION (provided by applicant): Cancer cells rely on oncogene-induced, hyper-proliferative signaling for growth and survival. c-Myc, a transcription factor which regulates cell cycle progression, cell growth and proliferation, is one of the most commonly overexpressed oncogenes in human cancer. Myc is overexpressed in 70% of human malignancies, including non-Hodgkin lymphoma, a cause of approximately 20,000 deaths in the United States each year. Despite decades of research into the functions and activity of Myc, much remains unresolved and there have been no successful therapies that target Myc to date. Recently, it has been proposed that targeting Myc indirectly may help overcome the lack of successful therapies for treating Myc-driven cancers. However, Myc regulation is highly complex and the identity and function of many of the proteins that regulate Myc activity remain unknown or poorly characterized. Thus, it is of critical importance to identify and evaluate proteins that interact wth Myc and regulate its function. We have preliminary data suggesting MTBP, a protein which we have previously shown to be linked to Myc-driven proliferation and lymphomagenesis, associates in a complex with Myc and regulates its oncogenic functions. Therefore, we hypothesize MTBP is a novel transcriptional regulator of Myc and has a critical role in lymphoma development and survival. To test this hypothesis, we propose two specific aims that utilize both in-vivo and in-vitro model systems. In the Aim 1, we will utilize molecular and biochemical strategies to elucidate the mechanism by which MTBP regulates Myc transcriptional activity. In Aim 2, we will employ in-vivo mouse model systems to evaluate the oncogenic activity of MTBP and characterize its role in lymphoma development and survival. We will also utilize human lymphoma cell lines to correlate our findings with mice to humans and to provide clinical relevance. Our results will significantly enhance our understanding of how Myc is regulated and will characterize the functions of a novel protein that regulates Myc. We anticipate that our findings will identify a novel target for treating Myc- driven malignancies. The challenging, comprehensive training that students in the MD/PhD program at the Vanderbilt University School of Medicine undergo will allow me to fulfill the goals of this proposal and will provide me with the education necessary to be a successful, independent physician-scientist. Throughout my training, I will learn to think critically, evaluate data, develop novel hypotheses and successfully answer scientific questions in the laboratory. This will be accomplished through seminars, journal clubs, didactic coursework, scientific meetings, analysis of the literature and thoughtful discussions with my mentor, thesis committee and other scientists. The educational and career development objectives outlined in this proposal will help me fulfill my goal of becoming a successful, independent physician-scientist in cancer research.