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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG025848-04
Application #
7487469
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Wise, Bradley C
Project Start
2005-09-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$121,230
Indirect Cost
Name
Duquesne University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004501193
City
Pittsburgh
State
PA
Country
United States
Zip Code
15282
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Parmar, Mayur S; Jaumotte, Juliann D; Wyrostek, Stephanie L et al. (2014) Role of ERK1, 2, and 5 in dopamine neuron survival during aging. Neurobiol Aging 35:669-79
Allen, Erika; Carlson, Kirsten M; Zigmond, Michael J et al. (2011) L-DOPA reverses motor deficits associated with normal aging in mice. Neurosci Lett 489:1-4
Flaherty, Patrick T; Chopra, Ishveen; Jain, Prashi et al. (2010) Identification of benzimidazole-based inhibitors of the mitogen activated kinase-5 signaling pathway. Bioorg Med Chem Lett 20:2892-6
Lin, Eva; Cavanaugh, Jane E; Leak, Rehana K et al. (2008) Rapid activation of ERK by 6-hydroxydopamine promotes survival of dopaminergic cells. J Neurosci Res 86:108-17
Cavanaugh, Jane E; Jaumotte, Juliann D; Lakoski, Joan M et al. (2006) Neuroprotective role of ERK1/2 and ERK5 in a dopaminergic cell line under basal conditions and in response to oxidative stress. J Neurosci Res 84:1367-75