Investigating the function of MTBP in lymphoma

描述（由申请人提供）：癌细胞依赖于癌基因诱导的过度增殖信号传导来生长和存活。c-Myc是一种调节细胞增殖的转录因子， 细胞周期进程、细胞生长和增殖是人类癌症中最常见的过表达癌基因之一。Myc在70%的人类恶性肿瘤中过表达，包括非霍奇金淋巴瘤，这是美国每年约20，000例死亡的原因。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，迄今为止还没有针对Myc的成功疗法。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调控是高度复杂的，并且许多调控Myc活性的蛋白质的身份和功能仍然未知或表征不佳。因此，鉴定和评价与Myc相互作用并调节其功能的蛋白质至关重要。我们有初步的数据表明MTBP，一种我们以前已经证明与Myc驱动的增殖和淋巴瘤发生有关的蛋白质，与Myc形成复合物并调节其致癌功能。因此，我们假设MTBP是一种新的Myc转录调节因子，在淋巴瘤的发展和生存中起着关键作用。为了验证这一假设，我们提出了两个具体的目标，利用体内和体外模型系统。在本研究中，我们将利用分子生物学的方法来阐明MTBP调控Myc转录活性的机制。在目标2中，我们将采用体内小鼠模型系统来评估MTBP的致癌活性并表征其在淋巴瘤发展和存活中的作用。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相关联，并提供临床相关性。我们的研究结果将显著增强我们对Myc是如何调节的理解，并将表征一种调节Myc的新型蛋白质的功能。我们预期我们的研究结果将确定一个新的目标，用于治疗Myc驱动的恶性肿瘤。 在医学的范德比尔特大学医学院的MD/PhD课程的学生接受具有挑战性的，全面的培训将使我能够实现这一建议的目标，并将为我提供必要的教育，成为一个成功的，独立的医生科学家。在我的培训中，我将学习批判性思考，评估数据，开发新的假设，并成功地回答实验室中的科学问题。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的深思熟虑的讨论来实现。在这个建议中概述的教育和职业发展目标将帮助我实现我的目标，成为一个成功的，独立的医生，科学家在癌症研究。

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.