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Harnessing microglia towards repair vs. damage: Does p38 MAPK hold the reins?

利用小胶质细胞进行修复与损伤：p38 MAPK 是否能掌控一切？

基本信息

批准号：
8231475
负责人：
ADAM D BACHSTETTER
金额：
$ 2.71万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2012-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231475
关键词：
Affect Aging Alzheimer&apos s Disease Amyloid beta-Protein Astrocytes Attenuated Brain Cells Chronic Degenerative Disorder Development Development Plans Disease Disease Progression Edema Educational workshop Effector Cell Encephalitis Environment Equilibrium Excision Family Foundations Functional disorder Future Genetic Goals Growth Growth Factor Homeostasis Immune Immune response Immune system Immunity Inflammation Inflammatory Inflammatory Response Infusion procedures Interleukin-12 International Intervention Investigation Knockout Mice Knowledge Laboratory Research Lead Learning MAP Kinase Gene MAP Kinase Modules MAPK14 gene Mentors Microglia Modeling Mus Neuraxis Neurodegenerative Disorders Neuroglia Neurons Nitrogen Operative Surgical Procedures Oxygen Pathogenesis Pathology Pathway interactions Peripheral Phase Play Preparation Process Production Protein Isoforms Protein Kinase Protein Secretion Publications Regulation Relative (related person)Research Research Personnel Research Proposals Rest Role Signal Transduction Stimulus Synapses System TNF gene Testing Therapeutic Training Transgenic Mice Transgenic Model Up-Regulation Validation age related base career career development cell type cytokine effective therapy experience genetic regulatory protein inhibitor/antagonist insight killings macrophage medical specialties meetings mouse model neuroinflammation neuron loss novel oxidative damage pathogen repaired response skills small molecule stressor therapeutic development therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): 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-12, TNF-1) 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 (A2). This proposal will test the hypothesis that the p381 MAP kinase signaling cascade leads to the detrimental forms of microglia activation, and that blocking the p381 pathway will decrease the detrimental responses of activated microglia without affecting the beneficial responses. Aim 1 will test the hypothesis that activation of the p381 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 p381 to test the hypothesis that suppression of p381 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 p381 in microglia vs. other neural cell types in the damage produced by A2. To test this aim, we will use an A2 infusion AD-relevant model in a mouse with a genetic deletion of p381 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 p381 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 career- enhancing 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.

描述（由申请人提供）：