The role of macrophage phenotype and age in spinal cord injury

巨噬细胞表型和年龄在脊髓损伤中的作用

• 批准号: 9145801
• 负责人: JOHN C GENSEL
• 金额: $ 32.39万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145801
• 关键词: Acute; Affect; Age; Age Factors; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Azithromycin; Biology; Cell Proliferation; Cells; Chronic; Clinical; Clinical Data; Contusions; Data; Development; Dose; Effectiveness; Equilibrium; Estradiol; Female; Flow Cytometry; Genes; Genetically Engineered Mouse; Goals; Gonadal Steroid Hormones; Healed; Health; Health Care Costs; Human; In Vitro; Incidence; Individual; Inflammatory; Inflammatory Response; Intervention; Investigation; Knockout Mice; Knowledge; Macrolide Antibiotics; Macrophage Activation; Mediating; Modeling; Mus; Outcome Measure; Paralysed; Pathology; Patients; Phenotype; Physiological; Process; Production; Progesterone; Publishing; Recovery; Recovery of Function; Research; Rodent; Role; Spinal cord injury; Techniques; Testing; Time; Tissues; United States; Work; Wound Healing; age effect; aged; arginase; axon growth; axon regeneration; base; clinical practice; clinically relevant; functional disability; gain of function; healing; improved; in vivo; injury and repair; innovation; loss of function; macrophage; male; middle age; mouse model; neuroinflammation; neuropathology; neuroprotection; neurotoxic; neurotoxicity; novel; pre-clinical; remyelination; repaired; response; sex; treatment strategy

 DESCRIPTION (provided by applicant): Spinal cord injury (SCI) triggers a heterogeneous neuroinflammatory response consisting of macrophages with the potential to both aggravate tissue damage and promote wound healing and repair. These macrophages have been identified as pro-inflammatory, pathological "M1" macrophages or anti-inflammatory, alternatively activated, pro-reparative "M2" macrophages. There is published evidence that driving M2 macrophage activation improves SCI recovery. The mechanisms underlying the reparative effects of M2 macrophages, however, are not well understood. As a result, the development of clinically viable, pharmacological interventions that harness the reparative potential of activated macrophages remains a critical challenge that is compounded by a changing SCI demographic. The incidence of SCI among older individuals has increased in recent years with a more equal balance of SCI across sexes. The purpose of this proposal is to investigate the mechanisms of M2 macrophage-mediated SCI repair and determine the effects of age and sex on SCI macrophage activation. Aim 1 will determine the role of arginase in M2 macrophage-mediated SCI repair processes through the use of genetically engineered mice with macrophages that lack arginase-1 (Arg1) and a newly identified treatment that increases M2-mediated arginase production. Parallel in vivo and in vitro SCI models of neurotoxicity, axon growth/dieback, and remyelination will test the hypothesis that the effects of M2 macrophages are dependent upon Arg1 production. In Aim 2 mice of different ages and sex will be used to determine the effect of these physiological factors on the acute SCI macrophage response. The macrophage response over time will be evaluated using newly developed focused gene profiling and flow cytometry techniques. The hypothesis to be tested is that aged males will have impaired M2 macrophage activation. In Aim 3, the effect of age and sex on M2 macrophage-mediated SCI repair and recovery will be evaluated using a clinically relevant mouse SCI model and a newly developed immunomodulatory SCI treatment. Forms of M2 macrophage activation occur in most CNS pathologies; therefore the current work is significant because it is expected to have broad translational impact on a wide range of neuroinflammatory conditions. This project is both conceptually and technically innovative. It will employ creative use of Arg1 knockout mice and a novel immunomodulatory agent. The investigation of the effects of age and sex on the macrophage response to SCI using a comprehensive focused gene array approach is novel. Collectively, the completion of the proposed research will improve scientific knowledge regarding macrophage biology as it specifically relates to age and sex. This knowledge will improve clinical practice by leading to sophistication of treatment strategies that include sex and age as potential influences in the context of SCI treatment and recovery.