Investigating the role of MTBP in aging using a novel mouse model

描述(申请人提供)：长寿父母的子女的死亡风险比他们的配偶低，因为他们共同的环境条件。此外，与年龄匹配的对照组相比，百岁老人的兄弟姐妹自己成为百岁老人的可能性更大。因此，虽然环境因素在衰老中起着重要作用，但有证据表明，寿命至少受到适度的基因控制。自20世纪80年代初以来，科学家们已经知道，在动物模型中，单基因突变可以延长寿命。自那以后，这项工作导致了几个基因、信号通路和细胞过程的发现，这些基因、信号通路和细胞过程对衰老至关重要。例如，与增殖相关的细胞代谢增加已知会增加活性氧物种(ROS)的形成、DNA损伤和复制应激，所有这些都是理论上导致衰老的因素。我们有初步数据表明，MTBP是一种我们最近发现的在调节癌症发展中很重要的蛋白质，也是一种新的增殖和衰老调节因子。我们假设MTBP调节导致衰老的增殖和细胞新陈代谢的有害影响。为了验证这一假设，我们提出了三个同时使用体外和体内方法的目标。在第一个目标中，我们计划表征涉及MTBP的新的蛋白质相互作用。在第二个目标中，我们将研究MTBP对与衰老有关的细胞过程的影响。在第三个目标中，我们将通过使用小鼠模型来评估MTBP在哺乳动物体内衰老中的作用。这项拟议研究的结果将进一步加深我们对支配衰老的生物过程以及MTBP在这些过程中的作用的理解。我们的工作可能会确定一种新的治疗靶点，以延缓衰老，促进健康衰老，并治疗和/或预防与年龄相关的疾病。范德比尔特大学医学院的教学医学/博士培训计划提供了一个支持性的环境，使我能够实现本研究计划的目标，并获得实现我在科学和医学方面的职业目标所需的培训。在我的训练中，我将学会批判性思维，让他人参与到科学话语中来，并创新地质疑未知。范德比尔特提供优秀的课程、研讨会和职业发展活动，以支持学员。我的赞助人Eischen博士还将提供宝贵的培训和关键的一对一指导，以确保在研究生院和其他地方取得成功。完成这个培训计划将帮助我实现我的职业目标，成为一名富有成效的内科科学家，关心病人，并进行生物医学研究，进一步加深我们对人类疾病和衰老的理解。

DESCRIPTION (provided by applicant): Children of long-lived parents have a lower mortality risk than their spouses, with whom they share environmental conditions. Furthermore, siblings of centenarians have a greater chance of becoming centenarians themselves, compared to age-matched controls. Thus, while environmental factors play an important part in aging, evidence suggests lifespan is at least under moderate genetic control. Since the early 1980s, scientists have known that mutations of single genes can extend lifespan in animal models. The work since has led to the discovery of several genes, signaling pathways, and cellular processes important for aging. For example, increased cellular metabolism associated with proliferation is known to increase the formation of reactive oxygen species (ROS), DNA damage, and replicative stress, all of which are theoretical contributors to aging. We have preliminary data to suggest that MTBP, a protein that we have recently shown is important in regulating cancer development, is also a novel regulator of proliferation and aging. We hypothesize that MTBP modulates the deleterious effects of proliferation and cellular metabolism that contribute to aging. To test this hypothesis, we propose three aims that use both in vitro and in vivo approaches. In the first aim, we plan to characterize novel protein interactions involving MTBP. In the second aim, we will examine the effect of MTBP on cellular processes implicated in aging. In the third aim, we will evaluate the role of MTBP in mammalian aging, in vivo, by using a mouse model. The results from the proposed study will further our understanding of the biological processes that govern aging and the role of MTBP in these processes. Our work is likely to identify a novel therapeutic target to retard aging, promote healthy aging, and treat and/or prevent age-related diseases. The didactic MD/PhD training plan at Vanderbilt University School of Medicine provides a supportive environment that will allow me to meet the goals of this research proposal and gain the training necessary to achieve my career goals in science and medicine. During my training, I will learn to think critically, engage others in scientific discourse, and innovatively question the unknown. Outstanding courses, seminars, and career development activities are provided at Vanderbilt to support trainees. My sponsor, Dr. Eischen, will also provide valuable training and critical one-on-one mentorship to ensure success in graduate school and beyond. Completing this training plan will help me meet my career goal of becoming a productive physician-scientist, who cares for patients and conducts biomedical research that furthers our understanding of human disease and aging.