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.

标题：CNS损伤后的免疫代谢调节 进行性神经变性是创伤性脑损伤（TBI）的后遗症，约2%的人口患有慢性神经功能缺损，包括认知障碍和痴呆，由先前的头部损伤引起。流行病学数据表明，TBI病史是痴呆的主要外在原因，包括发展阿尔茨海默病和相关痴呆（AD/ADRD）的风险增加;然而，将TBI与随后的神经变性（包括由于血管对认知障碍和痴呆（VCID）的贡献）联系起来的机制尚未确定。尽管CNS内存在免疫赦免，但一系列协调的空间和时间调节的脑免疫应答的发展与TBI后的过早认知老化、神经变性和VCID相关。我们的目标是测试总体假设，即脑代谢失调激活脑膜先天淋巴细胞（ILC），使慢性促炎级联反应永久化，最终导致神经退行性变和认知功能低下。具体而言，我们提出，能量传感器，5 '-AMP活化蛋白激酶（AMPK）的活性降低，诱导星形胶质细胞内的衰老相关分泌表型（SASP），以扩大促炎ILC，招募外周免疫细胞，并驱动创伤后痴呆。目的1将检验星形胶质细胞特异性AMPK激活限制神经变性的假设。研究将结合先进的遗传模型，神经影像学和空间蛋白基因组学，纵向定义TBI后特定区域和细胞类型的神经退行性变化。目的2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。研究将在功能上暗示脑膜ILC是脑免疫和进行性神经变性的关键介质，包括脑萎缩和TBI后的灰/白色物质损失。目的3将检验调节ILC 2减少进行性神经变性特征以减弱TBI后的慢性神经损伤的假设。研究将证明靶向脑膜ILC抑制神经变性的治疗潜力。预期成果：我们的机制研究将显示急性脑代谢紊乱引发有害的促炎级联反应，最终导致神经退行性变。具体来说，我们的概念创新研究将确定星形胶质细胞衰老作为整合脑代谢和慢性炎症的细胞会聚点。我们还将阐明一种新的细胞间通讯途径，即星形胶质细胞通过调节脑膜ILC来协调外周免疫。总之，我们的研究将显示中枢神经系统内的局部病理变化如何转化为特定的免疫反应，最终导致创伤后痴呆。临床意义：进行性神经变性导致慢性认知功能障碍，使患者生活质量恶化。通过证明调节性ILC 2作为抑制慢性炎症、限制神经变性和改善长期神经认知结果的新型基于细胞的疗法的可行性和功效，我们的研究将建立治疗创伤后痴呆、AD和相关进行性痴呆的治疗开发的概念框架。