Genetic Control of Microglia and Neural Macrophages

小胶质细胞和神经巨噬细胞的遗传控制

• 批准号: 8298485
• 负责人: WILLIAM S TALBOT
• 金额: $ 34.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298485
• 关键词: ATP phosphohydrolase; Affect; Apoptotic; Axon; Biochemical; Biological Assay; Cell Transplantation; Cells; Development; Diabetes Mellitus; Disease; Electron Microscopy; Functional disorder; Gays; Genes; Genetic; Genetic Screening; Goals; Image; Immune system; Infection; Injury; Investigation; Laboratories; Mammals; Microglia; Minocycline; Modeling; Molecular; Multiple Sclerosis; Mutate; Mutation; Mutation Analysis; Myelin; Myelin Sheath; Nervous System Physiology; Nervous system structure; Neuraxis; Neurobiology; Neuroglia; Neurons; Oligodendroglia; Paralysed; Pathology; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Phagocytes; Pharmaceutical Preparations; Phenotype; Play; Process; Ranvier' s Nodes; Rest; Role; Schwann Cells; Symptoms; Synaptic Vesicles; Testing; Therapeutic; Time; Tissues; Work; Zebrafish; abstracting; advanced disease; base; cell injury; cell motility; cell type; cytotoxic; diabetic; fighting; gene function; human disease; injured; insight; macrophage; migration; mutant; myelination; nervous system disorder; oxidative damage; pathogen; prevent; relating to nervous system; repaired; research study

Abstract This project will exploit the power of zebrafish genetics to discover new genes that are essential for the development, migration, and activation of microglia and neural macrophages. Microglia are highly motile, phagocytic glial cells within the central nervous system (CNS) that destroy pathogens and clear debris such as apoptotic cells and damaged axons. Macrophages perform similar functions in peripheral nerves. In disease or after injury, inappropriate activation of microglia and macrophages can cause damage to the nervous system. For example, in multiple sclerosis (MS) and other diseases in the CNS, activated microglia release cytotoxic factors that harm myelinated axons. Similarly, activated macrophages damage myelinated axons in diabetic peripheral neuropathy. Despite the importance of microglia and macrophages in the healthy and diseased nervous system, there are fundamental gaps in the understanding of the development, migration, and activation of these cells. Thus investigation of the mechanisms that regulate the function of microglia and neural macrophages will provide important insights into the pathophysiology of diseases of the nervous system, including MS, peripheral neuropathies, and many others. In addition, these studies will suggest new avenues toward therapies to prevent and repair damage to the nervous system. To discover new genes essential for the development and function of microglia and neural macrophages, we will conduct a genetic screen for mutations in which these cells are disrupted. Using a rapid, robust marker assay for microglia and macrophages, we have found that microglia and macrophages are increased and strongly activated in a mutant recovered in our previous screens for myelination mutants, nsf. Interestingly, a drug that blocks activation of microglia and macrophages ameliorates the phenotype of nsf mutants, suggesting that activated phagocytes contribute to pathology in these mutants. These results demonstrate the feasibility of finding mutations that affect microglia and neural macrophages, and also underscore the importance of the relationship between myelinated axons and the associated phagocytes. Analysis of additional mutants with abnormal microglia and macrophages will test the hypothesis that activation of these cells contributes to diverse pathologies of the nervous system, such that they act to exacerbate and ameliorate symptoms in different contexts. This project will isolate more mutations in genes with essential functions in microglia and macrophages and characterize the functions of these genes at the cellular and biochemical level. These experiments will elucidate fundamental aspects of vertebrate neurobiology, establish zebrafish models of important human diseases, add to the understanding of the processes that are disrupted in diseased and injured axons, and provide a basis to pursue the therapeutic repair of damage to the nervous system.

抽象的 该项目将利用斑马鱼遗传学的力量来发现对于斑马鱼至关重要的新基因 小胶质细胞和神经巨噬细胞的发育、迁移和激活。小胶质细胞运动能力很强， 中枢神经系统 (CNS) 内的吞噬细胞胶质细胞可消灭病原体并清除碎片，例如 凋亡细胞和受损的轴突。巨噬细胞在周围神经中发挥类似的功能。在疾病或 受伤后，小胶质细胞和巨噬细胞的不当激活会导致神经系统受损。 例如，在多发性硬化症 (MS) 和其他中枢神经系统疾病中，激活的小胶质细胞释放细胞毒素 损害有髓轴突的因素。同样，激活的巨噬细胞会损害糖尿病患者的有髓轴突 周围神经病变。尽管小胶质细胞和巨噬细胞对于健康和患病的人都很重要 神经系统，对发育、迁移和神经系统的理解存在根本差距 激活这些细胞。因此，研究调节小胶质细胞功能的机制和 神经巨噬细胞将为神经疾病的病理生理学提供重要的见解 系统，包括多发性硬化症、周围神经病等。此外，这些研究将提出新的 预防和修复神经系统损伤的治疗途径。 发现小胶质细胞和神经细胞发育和功能所必需的新基因 巨噬细胞，我们将对这些细胞被破坏的突变进行基因筛查。使用 对小胶质细胞和巨噬细胞进行快速、稳健的标记分析，我们发现小胶质细胞和巨噬细胞 在我们之前的髓鞘形成突变体筛选中回收的突变体中增加并强烈激活， 国家科学基金会。有趣的是，一种阻止小胶质细胞和巨噬细胞激活的药物可以改善 nsf 的表型 突变体，表明活化的吞噬细胞有助于这些突变体的病理学。这些结果 证明寻找影响小胶质细胞和神经巨噬细胞的突变的可行性，并且 强调有髓轴突和相关吞噬细胞之间关系的重要性。 对具有异常小胶质细胞和巨噬细胞的其他突变体的分析将检验激活的假设 这些细胞导致神经系统的多种病理，从而加剧和 改善不同情况下的症状。该项目将分离出更多具有必需基因的突变 在小胶质细胞和巨噬细胞中发挥功能，并表征这些基因在细胞和细胞中的功能 生化水平。这些实验将阐明脊椎动物神经生物学的基本方面，建立 重要人类疾病的斑马鱼模型，增加了对在疾病中被破坏的过程的理解 患病和受伤的轴突，并为神经损伤的治疗性修复提供基础 系统。