Kinase Signaling in Aging Dopamine Neurons

描述（由申请人提供）：我的主要职业目标是作为一名独立的科学家，利用体内和体外的方法研究衰老作为中枢神经系统疾病（包括神经退行性疾病）的危险因素，并在老年学领域获得更广泛的知识。我的职业发展计划包括获得专业技能、管理技能、拨款写作技能和新的研究技术，以确保我作为一名独立研究者的成功。匹兹堡大学为实现这些目标提供了良好的环境，随时可以接触到老龄化、老年学和神经变性领域的世界级研究人员。此外，还有许多大学资源，包括期刊俱乐部，研讨会，生存技能和道德项目，以及学术职业发展办公室，这些都将帮助我实现我的职业目标。

DESCRIPTION (provided by applicant): My primary career goal is to have an academic career as an independent scientist using in vivo and in vitro approaches to study aging as a risk factor for CNS diseases, including neurodegenerative diseases, and to gain a broader knowledge in the field of gerontology. My career development plan includes acquiring professional skills, supervisory skills, grant writing skills, and new research techniques to ensure my success as an independent investigator. The University of Pittsburgh provides an excellent environment to attain these goals, with ready access to world class researchers in the fields of aging, gerontology and neurodegeneration. Moreover, there are many university resources, including journal clubs, seminars, the Survival Skills and Ethics Program, and the Office of Academic Career Development that will help me achieve my career goals. Cells in the brain possess a propensity to die which increase with aging. Fortunately, cells have a variety of mechanisms to block this cell death. Neuronal death may be inhibited by neurotrophin-mediated activation of the mitogen-activated protein kinase (MAPK) pathways, such as extracellular signal regulated kinases 1, 2, and 5 (ERK1/ 2 and ERK5). We propose to test the hypothesis that neurotrophins protect neurons from oxidative stress via the activation of ERK1/2 and ERK5, and the capacity of neurotrophins to provide protection decreases with age due, in part, to a decreased ability to activate ERK1/2 and ERK5. We will study the contributions of ERK1/2 and ERK5 to neuronal survival with aging using a specific cell type (dopamine neurons) exposed to a selective toxin (6-hydroxydopamine) to produce a specific insult (oxidative stress) in the following specific aims: (1) Determine the role of ERK1/2 and ERK5 signaling pathways in GDNF-mediated neuronal survival from 6- OHDA-induced oxidative stress. (2) Determine the impact of aging on the vulnerability of dopaminergic neurons to 6-OHDA-induced oxidative stress. (3) Determine the consequence of aging on ERK1/2 and ERK5 signaling pathway expression and activation in striatum and substantia nigra. These studies will advance our understanding of the role of MAPK cascades in neuronal vulnerability with normal aging and may also elucidate mechanisms by which neurons die in neurodegenerative diseases. The research experience gained will help me achieve my overall career goal to continue in an academic environment as an independent scientist.