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.

Public Health Relevance

This project will evaluate the role of a novel molecular pathway in the biological process of aging. Our studies will improve understanding of aging biology and the development of diseases associated with aging. The results from the proposed experiments are expected to provide potential targets for future therapeutic intervention.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F05-C (20))
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Velazquez, Jose M
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Vanderbilt University Medical Center
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Grieb, Brian C; Boyd, Kelli; Mitra, Ramkrishna et al. (2016) Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice. Aging (Albany NY) 8:2590-2602
Thomas, L R; Foshage, A M; Weissmiller, A M et al. (2016) Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif. Oncogene 35:3613-8
Thomas, Lance R; Wang, Qingguo; Grieb, Brian C et al. (2015) Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. Mol Cell 58:440-52
Grieb, Brian C; Gramling, Mark W; Arrate, Maria Pia et al. (2014) Oncogenic protein MTBP interacts with MYC to promote tumorigenesis. Cancer Res 74:3591-602
Grieb, Brian C; Chen, Xi; Eischen, Christine M (2014) MTBP is overexpressed in triple-negative breast cancer and contributes to its growth and survival. Mol Cancer Res 12:1216-24
Meda, Shashwath A; Koran, Mary Ellen I; Pryweller, Jennifer R et al. (2013) Genetic interactions associated with 12-month atrophy in hippocampus and entorhinal cortex in Alzheimer's Disease Neuroimaging Initiative. Neurobiol Aging 34:1518.e9-18