Immunometabolic regulation after CNS injury

中枢神经系统损伤后的免疫代谢调节

• 批准号: 10737334
• 负责人: KRISHNAN M. DHANDAPANI
• 金额: $ 197.53万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737334
• 关键词: 5' -AMP-activated protein kinase; Acquired Immunodeficiency Syndrome; Acute; Adopted; Aging; Alzheimer' s Disease; Anatomy; Astrocytes; Brain; Categories; Cause of Death; Cell Aging; Cell Communication; Cell Therapy; Cells; Cerebral meninges; Cerebrospinal Fluid; Cerebrum; Chronic; Cognitive aging; Craniocerebral Trauma; Dementia; Development; Dura Mater; Exhibits; FDA approved; Foundations; Immune; Immune response; Immunity; Immunomodulators; Impaired cognition; Impairment; Individual; Infiltration; Inflammaging; Inflammation; Inflammatory; Intervention; Knowledge; Lymphoid Cell; Meningeal; Metabolic; Metabolic dysfunction; Metabolism; Metformin; Multiple Sclerosis; Mus; Nerve Degeneration; Nervous System Trauma; Neurologic; Neurologic Dysfunctions; Organ; Outcome; Parkinson Disease; Pathologic; Peripheral; Phenotype; Phosphotransferases; Population; Public Health; Quality of life; Regulation; Resolution; Route; Series; Signaling Protein; Spinal cord injury; Sterility; TBI Patients; Testing; Therapeutic; Translating; Traumatic Brain Injury; aging population; anaerobic glycolysis; central nervous system injury; clinically significant; disability; improved; improved outcome; in vivo; innovation; innovative technologies; long-term sequelae; malignant breast neoplasm; neuroinflammation; novel; novel therapeutic intervention; persistent symptom; post stroke; prevent; progressive neurodegeneration; recruit; restraint; senescence; sensor; therapeutic development

Title: Immunometabolic regulation after CNS injury Progressive neurodegeneration is a sequela of traumatic brain injury (TBI), with ~2% of the population living with chronic neurological deficits, including cognitive impairment and dementia, caused by a prior head injury. Epidemiological data indicate a history of TBI is the leading extrinsic cause of dementia, including a heightened risk of developing Alzheimer’s disease and related dementias (AD/ADRD); however, the mechanisms linking TBI with subsequent neurodegeneration including due to vascular contribution to cognitive impairment and dementia (VCID) are undefined. Despite immune privilege within the CNS, development of a coordinated series of spatially- and temporally-regulated cerebral immune responses correlates with premature cognitive aging, neurodegeneration and VCID after TBI. Our objective is to test the overarching hypothesis that cerebral metabolic dysregulation activates meningeal innate lymphoid cells (ILCs) to perpetuate a chronic, pro-inflammatory cascade that culminates in neurodegeneration and poor cognitive outcomes. Specifically, we propose that reduced activity of the energetic sensor, 5’-AMP-activated protein kinase (AMPK), induces a senescence-associated secretory phenotype (SASP) within astrocytes to expand pro-inflammatory ILCs, recruit peripheral immune cells, and drive post-traumatic dementia. Aim 1 will test the hypothesis that astrocyte-specific AMPK activation limits neurodegeneration. Studies will incorporate advanced genetic models, neuroimaging, and spatial proteogenomics to longitudinally define region- and cell type-specific neurodegenerative changes after TBI. Aim 2 will test the hypothesis that astrocyte-specific AMPK activation restrains pro-inflammatory meningeal ILC expansion. Studies will functionally implicate meningeal ILCs as critical mediators of cerebral immunity and progressive neurodegeneration, including cerebral atrophy and grey/white matter loss, after TBI. Aim 3 will test the hypothesis that regulatory ILC2 reduce the progressive neurodegenerative profile to attenuate chronic neurological injury after TBI. Studies will demonstrate the therapeutic potential of targeting meningeal ILCs to restrain neurodegeneration. Expected outcomes: Our mechanistic studies will show acute cerebral metabolic derangements initiate a deleterious, pro-inflammatory cascade that culminates in neurodegeneration. Specifically, our conceptually innovative studies will identify astrocyte senescence as a cellular convergence point that integrates cerebral metabolism and chronic inflammation. We also will elucidate a novel route of cell-cell communication whereby astrocytes coordinate peripheral immunity via regulation of meningeal ILCs. Together, our studies will show how local pathological changes within the CNS are translated into context-specific immune responses that culminate in post-traumatic dementia. Clinical significance: Progressive neurodegeneration causes chronic cognitive dysfunction to worsen patient quality of life. By demonstrating the feasibility and efficacy of regulatory ILC2 as a novel, cell- based therapy to restrain chronic inflammation, limit neurodegeneration, and improve long-term neurocognitive outcomes, our studies will establish a conceptual framework for therapeutic development to treat post-traumatic dementia, AD, and related progressive dementias.

题目：中枢神经系统损伤后的免疫代谢调节 进行性神经退行性变是创伤性脑损伤 (TBI) 的后遗症，大约 2% 的人患有慢性神经功能障碍，包括由先前的头部损伤引起的认知障碍和痴呆。流行病学数据表明，TBI 病史是主要的外在因素。痴呆症的病因，包括罹患阿尔茨海默氏病和相关痴呆症 (AD/ADRD) 的全部风险；然而，TBI 与随后的神经退行性变的机制，包括血管导致认知障碍和痴呆症 (VCID)；尽管中枢神经系统内的免疫特权尚未明确，但一系列协调的空间和时间调节的大脑免疫反应的发展与 TBI 后的过早认知衰老、神经退行性变和 VCID 相关。脑膜先天淋巴样细胞（ILC）使慢性促炎症级联持续存在，最终导致神经退行性变和认知结果不良，具体来说，我们建议能量传感器的活动减少， 5'-AMP 激活蛋白激酶 (AMPK) 在星形胶质细胞内诱导衰老相关的分泌表型 (SASP)，以扩大促炎性 ILC、招募外周免疫细胞并驱动创伤后痴呆，目标 1 将检验以下假设：星形胶质细胞特异性 AMPK 激活限制神经退行性变。研究将结合先进的遗传模型、神经影像学和空间蛋白质组学来纵向定义 TBI 后区域和细胞类型特异性的神经退行性变化。目标 3 将检验星形胶质细胞特异性 AMPK 激活抑制促炎性脑膜 ILC 扩张的假设。检验调节性 ILC2 减少进行性神经退行性病变以减轻 TBI 后慢性神经损伤的假设。 研究将证明靶向脑膜 ILC 来抑制的治疗潜力。预期结果：我们的机制研究将表明，急性脑代谢紊乱会引发有害的促炎症级联反应，最终导致神经退行性变。具体而言，我们的概念性创新研究将确定星形胶质细胞衰老是整合脑代谢和慢性炎症的细胞汇聚点。我们还将阐明一种新的细胞间通讯途径，星形胶质细胞通过调节脑膜 ILC 来协调外周免疫，我们的研究将共同​​展示其中的局部病理变化。中枢神经系统被转化为特定环境的免疫反应，最终导致创伤后痴呆。临床意义：通过证明调节性 ILC2 作为一种新型的基于细胞的可行性和有效性，渐进性神经退行性疾病会导致慢性认知功能障碍，从而恶化患者的生活质量。为了抑制慢性炎症、限制神经退行性变和改善长期神经认知结果，我们的研究将为治疗创伤后痴呆、AD 和相关进行性痴呆的治疗开发建立一个概念框架。