Fellowship for Adam Bachstetter: Harnessing microglia toward repair vs. damange: Does p38 MAPK hold the reins?

Grants and Contracts Details


A primary pathological component of Alzheimer's disease (AD) is brain inflammation. Activation of microglia, the “macrophages of the brain”, is known to occur in AD and believed to contribute to the neuronal damage. Studies of peripheral macrophages have determined that multiple distinct activation states of macrophages exist, and recent studies have confirmed these findings in microglia. Macrophages/microglia can be broadly defined as being classically activated or alternatively activated. Classically activated macrophages are typified by the release of proinflammatory cytokines (e.g. IL-1â, TNF-á) and reactive oxygen and nitrogen species, which are components of the inflammatory response that is known to cause neuronal damage. However, not all forms of microglia activation are detrimental. Some forms of microglia activation are beneficial, such as alternative activation responses that lead to removal or clearance of amyloid beta (Aâ). This proposal will test the hypothesis that the p38á MAP kinase signaling cascade leads to the detrimental forms of microglia activation, and that blocking the p38á pathway will decrease the detrimental responses of activated microglia without affecting the beneficial responses. Aim 1 will test the hypothesis that activation of the p38á MAP kinase signaling cascade occurs in microglia during the early phase of pathogenesis in an AD-relevant transgenic mouse model (the Tg6799 mouse). Aim 2 will use a novel, brain-penetrant, small molecule inhibitor of p38á to test the hypothesis that suppression of p38á activity will slow the pathology in the Tg6799 mouse. This aim will provide training in the use of pharmacological tools, transgenic models of neurodegenerative disease, and therapeutic target validation. Aim 3 will evaluate the relative contribution of p38á in microglia vs. other neural cell types in the damage produced by Aâ. To test this aim, we will use an Aâ infusion AD-relevant model in a mouse with a genetic deletion of p38á only in the microglia. This aim will provide training in the use of conditional knockout mouse models using the cre/lox system, and stereotaxic surgery in mice. Successful completion of this project will provide mechanistic insight into how the key regulatory protein p38á is involved in CNS pathophysiology mechanisms and intervention responses, and will form the foundation for follow-on CNS therapeutic development campaigns targeting this important protein kinase. A Career Development Plan has been formalized, and includes a combination of formal classroom and specialty workshop participation, regular presentations of proposed research plans and results at the laboratory and research group level, presentation of independent research results in seminar format, participation in national and international scientific meetings, preparation of research proposals and publications, and development of additional careerenhancing skills. An experienced mentor, a rich scientific environment, and an organized educational and training plan will assure that the applicant has optimal opportunities for scientific growth, career enhancement and development into an independent academic investigator.
Effective start/end date4/15/109/14/12


  • National Institute on Aging: $27,055.00


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