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: 8856378
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856378
• 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; Health; 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; genetic approach; human disease; in vivo; indexing; inhibitor/antagonist; macrophage; mouse model; mutant; neurodevelopment; neuroinflammation; neuron loss; nigrostriatal pathway; postnatal; receptor; relating to nervous system; research study; response; sertoli cell; two-photon

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）：控制中枢神经系统（CNS）炎症沉淀或加剧大量使人类疾病的缺陷，但是我们对调节神经炎症的基本机制的理解是不完整的。小胶质细胞是大脑和脊髓的独特组织巨噬细胞，是其中的关键参与者 过程。这些前哨细胞展示了两种活性，这些活性是维持神经稳态的基础 - （i）免疫监测和（ii）凋亡细胞（ACS）和膜的吞噬作用。中枢神经系统以外的巨噬细胞的研究表明，这两种活动均通过通过TAM受体酪氨酸激酶发出信号来严格控制。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 - 显着 - 未知。该提案的实验解决了这个问题。在AIM 1中，依赖于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信号传导在健康哺乳动物大脑中连续发生的ACS的稳态，非炎性吞噬作用中的重要性。在AIM 2中，将使用类似的方法以及体内小胶质细胞的共聚焦和两光子成像，用于确定TAM信号传导在局部吞噬作用中的作用，这些作用是突触修剪的局部吞噬作用，以及突触修剪的基础，并在后神经后发育中进行神经元连接的重塑。在AIM 3中，将对TAM受体和缺陷型小鼠进行一系列促炎性挑战，以确定是否抑制 小胶质细胞中的先天炎症反应在TAM控制下，就像在免疫系统的细胞中一样。最后，在AIM 4中，从较早的目标中获得的知识将用于研究TAM调节在神经变性中所起的作用，如帕金森氏病的急性和渐进小鼠模型所评估。总之，这些研究将描述中枢神经系统中免疫稳态的新途径的基本分子，细胞和生理特征，并有可能将TAM受体和配体鉴定为神经炎性和神经性疾病的治疗性干预的新靶标。