2005 — 2009 |
Cavanaugh, Jane E |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Kinase Signaling in Aging Dopamine Neurons @ University of Pittsburgh At Pittsburgh
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.
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2014 |
Cavanaugh, Jane E |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
Novel Small Molecule Inhibitors of Mek5_erk5 For the Treatment of Breast Cancer
Project Summary/Abstract Dyregulation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositide-3-kinase (PI3K) pathways has been implicated in breast cancer pathology. Activation of the MEK1/2-ERK1/2 MAPK and the PI3K/Akt cascades in breast cancer increases cell proliferation and sustains tumor survival. Further, interaction between these pathways has been implicated in chemoresistance, suggesting that dual inhibition of these pathways may be necessary to prevent breast cancer growth and metastasis. The newest member of the MAPK family of kinases, the MEK5-ERK5 pathway, has been shown to enhance cancer cell growth and increase patient mortality. More specifically, increased ERK5 activation has been associated with decreased disease-free survival in breast cancer patients and signaling crosstalk with the PI3K pathway has been demonstrated in other cancer models. Therapies that target the MEK1/2-ERK1/2 pathways are used clinically and inhibitors of the PI3K/Akt pathway are in Phase I and II clinical trials for breast cancer. While there are currently 3 small molecule inhibitors of MEK5-ERK5 signaling available only one has been tested in breast cancer models. Moreover, in some breast cancer cells, these inhibitors are not specific for the MEK5-ERK5 pathway and, in some cases, even increase ERK5 activation. Therefore, there is a need for novel small molecule inhibitors that are specific for the MEK5-ERK5 pathway that may be clinically useful alone or in combination with other kinase inhibitors. The goal of this proposal is to test small molecule inhibitors of MEK5 that we developed in in vitro and in vivo breast cancer models and to use these novel inhibitors and biochemical methods to examine crosstalk between the MEK5-ERK5 and PI3K/Akt pathways in breast carcinoma. Therefore, the aims of this proposal seek to test the hypothesis that novel small molecule inhibitors of MEK5-ERK5 decrease tumorigenesis, migration, and metastasis and enhance the anti-proliferative effects of PI3K/Akt inhibitors in breast cancer. Breast cancer cell lines with distinct hormonal profiles will be employed and a breast cancer-xenograph mouse model will be used to examine the effect of the MEK5 inhibitors on breast tumor progression and metastasis. The experiments proposed in this application will provide a greater mechanistic understanding of the MEK5-ERK5 pathway, potentially leading to the development of novel, targeted therapeutics for breast cancer patients. Further, a more comprehensive understanding of the MEK5-ERK5 pathway may have widespread implications for various cancer types, adding to the significance of the proposal. These aims will also provide a stimulating training opportunity for undergraduate and graduate students to actively participate in the research and discovery processes to improve our understanding of signal transduction in cancer biology.
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