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

• 批准号: 8615692
• 负责人: Greg E Lemke
• 金额: $ 42.44万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 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/8615692
• 关键词: Acute; Address; Alzheimer' 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

PROJECT SUMMARY/ABSTRACT 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.

项目摘要/摘要 控制中枢神经系统（CNS）炎症沉淀的缺陷或 加剧了大量使人类疾病衰弱的人，但我们对基本的理解 调节神经炎症的机制不完整。小胶质细胞，独特 大脑和脊髓的组织巨噬细胞是此过程中的关键参与者。这些 前哨细胞显示两种对维持神经至关重要的活动 稳态 - （i）免疫监视和（ii）凋亡细胞的吞噬作用（ACS） 和膜。中枢神经系统以外的巨噬细胞的研究表明 这两种活动都严格通过通过TAM受体酪氨酸发出信号来控制 激酶。尽管小胶质细胞也显着表达了TAM受体，但 TAM信号对CNS中小胶质细胞激活和功能的重要性是 - 值得注意的 - 未知。该提案的实验解决了这个问题。在AIM 1中， 依赖TAM受体和配体小鼠突变体的遗传和细胞生物学方法 将用于评估TAM信号传导在稳态，非 - 的重要性 在健康哺乳动物中不断发生的AC的炎症性吞噬作用 脑。在AIM 2中，类似的方法，以及共焦和两光子成像的类似方法 小胶质细胞在体内将用于确定TAM信号在局部的作用 吞噬作用是突触修剪和神经元重塑的基础的吞噬作用 产后神经发育的联系。在AIM 3中，一系列亲和反 炎症挑战将应用于TAM受体和缺陷小鼠的炎症挑战 确定小胶质细胞中先天炎症反应的抑制是否在TAM下 控制，就像免疫系统的细胞中一样。最后，在目标4中，知识获得了 从较早的目标中将应用于调查TAM监管在 神经变性，如在急性和进行性小鼠模型中所评估的 帕金森氏病。总之，这些研究将描绘基本的分子，细胞， 以及从根本上是免疫稳态的新途径的生理特征 中枢神经系统，并有可能将TAM受体和配体识别为新目标 神经炎症和神经退行性疾病的治疗干预。