TAM receptor control of microglial function and nervous system homeostasis

TAM 受体控制小胶质细胞功能和神经系统稳态

基本信息

批准号：
8732718
负责人：
Greg E Lemke
金额：
$ 42.01万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732718
关键词：
Acute Address Alzheimer&apos s Disease Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Behavioral Biological Brain Brain Injuries Cell membrane Cells Cessation of life Chronic Circadian Rhythms Coupled Dendritic Cells Development Employee Strikes Event Excision Eye Family Feedback Functional disorder Genes Genetic Glycocalyx Hippocampus (Brain)Homeostasis Human Image Immune Immune response Immune system Immunologic Surveillance Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Response Inherited Injury Knowledge Label Life Ligands Literature Maintenance Methods Microglia Modeling Molecular Molecular Genetics Multiple Sclerosis Mus Mutant Strains Mice Mutate Nerve Degeneration Nervous System Physiology Neuraxis Neurodegenerative Disorders Neurons Neurophysiology - biologic function Neurotoxins Parkinson Disease Pathway interactions Phagocytes Phagocytosis Photoreceptors Physiological Play Process Production Protein S Proteins Public Health Receptor Protein-Tyrosine Kinases Receptor Signaling Recovery Regulation Role Sentinel Series Signal Transduction Spinal Cord Stimulus Stress Structure of retinal pigment epithelium Synapses System Testing Testis Thalamic structure Therapeutic Intervention Time Tissues Transgenic Mice Variant Virus Diseases adult neurogenesis alpha synuclein autism spectrum disorder base cell type central nervous system injury cytokine design disease phenotype human disease in vivo indexing inhibitor/antagonist macrophage mouse model mutant neurodevelopment neuroinflammation neuron loss nigrostriatal pathway postnatal public health relevance receptor relating to nervous system research study response sertoli cell two-photon

项目摘要

DESCRIPTION (provided by applicant): Deficiencies in the control of central nervous system (CNS) inflammation precipitate or exacerbate a plethora of debilitating human diseases, yet our understanding of the basic mechanisms that regulate neuroinflammation is incomplete. Microglia, the distinctive tissue macrophages of the brain and spinal cord, are key players in this process. These sentinel cells display two activities that are fundamental to the maintenance of neural homeostasis - (i) immune surveillance and (ii) the phagocytosis of apoptotic cells (ACs) and membranes. Studies of macrophages outside of the CNS have demonstrated that both of these activities are strictly controlled by signaling through TAM receptor tyrosine kinases. Although TAM receptors are also prominently expressed by microglia, the importance of TAM signaling to microglial activation and function in the CNS is - remarkably - unknown. The experiments of this proposal address this question. In Aim 1, genetic and cell biological methods that rely on TAM receptor and ligand mouse mutants will be used to assess the importance of TAM signaling in the homeostatic, non- inflammatory phagocytosis of ACs that occurs continuously in the healthy mammalian brain. In Aim 2, similar methods, coupled with confocal and two-photon imaging of microglia in vivo, will be used to determine the role of TAM signaling in the localized phagocytosis that underlies synaptic pruning and the remodeling of neuronal connections in postnatal neural development. In Aim 3, a series of pro- and anti- inflammatory challenges will be applied to TAM receptor- and ligand-deficient mice to determine if inhibition of the innate inflammatory response in microglia is under TAM control, as it is in cells of the immune system. Finally, in Aim 4, the knowledge gained from the earlier aims will be applied to investigate the role that TAM regulation plays in neurodegeneration, as assessed in both acute and progressive mouse models of Parkinson's disease. Together, these studies will delineate the basic molecular, cellular, and physiological features of a fundamentally new pathway of immune homeostasis in the CNS, and potentially identify TAM receptors and ligands as new targets for therapeutic intervention in neuroinflammatory and neurodegenerative disease.

描述（由申请人提供）：中枢神经系统（CNS）炎症控制的缺陷会引发或加剧大量使人衰弱的人类疾病，但我们对调节神经炎症的基本机制的理解并不完整。小胶质细胞是大脑和脊髓的独特组织巨噬细胞，是这一过程的关键参与者过程。这些前哨细胞表现出两种对于维持神经稳态至关重要的活动 - (i) 免疫监视和 (ii) 凋亡细胞 (AC) 和细胞膜的吞噬作用。对 CNS 之外的巨噬细胞的研究表明，这两种活性均受到 TAM 受体酪氨酸激酶信号传导的严格控制。尽管小胶质细胞也显着表达 TAM 受体，但 TAM 信号传导对中枢神经系统小胶质细胞激活和功能的重要性尚不清楚。该提案的实验解决了这个问题。在目标 1 中，将使用依赖 TAM 受体和配体小鼠突变体的遗传和细胞生物学方法来评估 TAM 信号传导在健康哺乳动物大脑中持续发生的 AC 稳态、非炎症吞噬作用中的重要性。在目标 2 中，类似的方法，加上体内小胶质细胞的共聚焦和双光子成像，将用于确定 TAM 信号在局部吞噬作用中的作用，局部吞噬作用是突触修剪和出生后神经发育中神经元连接重塑的基础。在目标 3 中，将对 TAM 受体和配体缺陷的小鼠进行一系列促炎和抗炎挑战，以确定是否抑制小胶质细胞中的先天炎症反应受到 TAM 的控制，就像免疫系统细胞中的情况一样。最后，在目标 4 中，从早期目标中获得的知识将应用于研究 TAM 调节在神经退行性变中的作用，并在帕金森病的急性和进行性小鼠模型中进行评估。这些研究将共同描绘中枢神经系统中免疫稳态的全新途径的基本分子、细胞和生理特征，并有可能将 TAM 受体和配体确定为神经炎症和神经退行性疾病治疗干预的新靶点。