Role of a novel risk loci HAVCR2 of late-onset Alzheimer's disease in the regulation of microglial response in neurodegeneration

迟发性阿尔茨海默病的新风险位点 HAVCR2 在调节神经退行性小胶质细胞反应中的作用

• 批准号: 10608400
• 负责人: Oleg Butovsky
• 金额: $ 83.13万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608400
• 关键词: Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Animal Model; Antibodies; Antigen Presentation; Antigens; Area; Autoimmune Diseases; Basic Science; Behavior; Binding; Blocking Antibodies; Brain; Cell physiology; Chronic; Cognitive; Data; Dementia; Dendritic Cells; Deposition; Development; Disease; Disease Progression; Disease associated microglia; Genetic; Goals; Human; Immunity; Investigation; Laboratories; Late Onset Alzheimer Disease; Ligands; Link; Maintenance; Malignant Neoplasms; Microglia; Modeling; Mus; Myeloid Cell Activation; Myeloid Cells; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Onset of illness; Outcome; Pathology; Phagocytes; Phagocytosis; Phenotype; Phosphorylation; Play; Receptor Signaling; Regulation; Role; Signal Induction; Signal Transduction; T-Lymphocyte; TGFB1 gene; Tauopathies; Transcript; Translating; Tumor Immunity; Viral Cancer; Virus Diseases; Work; aging brain; cancer clinical trial; cancer therapy; cytokine; drug candidate; exhaustion; genetic linkage; genetic risk factor; genome wide association study; glial activation; immunoregulation; improved; induced pluripotent stem cell; mouse model; neuroinflammation; novel; novel therapeutic intervention; pharmacologic; response; restraint; risk variant; synergism; therapy development

PROJECT SUMMARY Recent largest GWAS identified HAVCR2 (TIM3) genetic risk factor for late-onset Alzheimer’s disease (LOAD). Our laboratory discovered and cloned Tim3 as an inhibitory molecule that induces T cell exhaustion in cancer1. Blocking antibodies to Tim3 are being approved for the treatment of cancer. However, we have now identified that Tim3 is not only expressed on T cells, but also on myeloid cells and dendritic cells, where TIM3 restrains dendritic cell function and regulate anti-tumor immunity2. In the CNS, HAVCR2 was identified as one of the top 100 enriched transcripts and is specifically expressed in both mouse and human microglia3-5, but its role and function in microglia is unknown. Our long-term goal is to define the role of TIM3 in regulation of microglia in neurodegeneration. We made the following observations: 1) Tim3 inhibits microglial activation and phagocytosis: deletion of Tim3 in dendritic cells boosted antigen presentation and we find that TIM3 also regulates microglial activation and phagocytosis; 2) TGFb-Tim3 axis regulates microglia phenotype switch in neurodegeneration: we find that TGFb is the key driver for the induction of Tim3 and once expressed it synergizes with TGFBR to potentiate TGFB signaling, loss of Tim3 switches M0-homeostatic microglia to an MGnD-nondegenerative phenotype; and 3) TIM3 deletion in microglia reduces plaque burden in 5xFAD mice. These data support the genetic linkage studies and show the importance of Tim3 in regulating disease pathology in AD by modulating microglial function. Based on these studies, we hypothesize that TIM3 is a key regulatory molecule in microglia that inhibits their response to neurodegeneration, migratory and phagocytic functions and thereby inhibit plaque clearance resulting in promotion of Ab deposition, development, and progression of AD in aging brain. Based on this hypothesis we have proposed three aims: Aim 1: Define how TIM3 regulates phenotype and functions in 5xFAD and P301S mouse AD models. We propose to study the effect of microglial deletion of Tim3 in neurodegeneration and brain tauopathy using the mouse models of AD. Aim 2: What is the role of TGFb signaling in the regulation of Tim3 expression and function in microglia and development of AD? Since TGFb plays a critical role in maintenance of the homeostatic phenotype in microglia, we propose to study how TGFb signaling induces Tim3 expression and promotes homeostatic behavior of microglia by cooperating with TGFb receptor signaling. Aim 3: Define the role of TIM3 in the regulation of human microglial function in AD. Determine how TIM3 impacts human iPSC-derived microglia activation and functions. We will examine whether genetic or pharmacologic inhibition of TIM3 has a similar effect on iPSCs-derived human microglia expressing the MGnD phenotype by utilizing a humanized chimeric mouse model of AD for treatment with human anti-Tim3 antibody IN SUMMARY, targeting TIM3 in microglia may provide a novel approach for therapeutic modulation of innate immunity in AD and dementia.

项目摘要 最近最大的GWAS确定了晚发性阿尔茨海默病（LOAD）的HAVCR 2（TIM 3）遗传风险因子。 我们的实验室发现并克隆了Tim 3作为一种抑制性分子，可诱导癌症中的T细胞耗竭1。 Tim 3的阻断抗体正被批准用于治疗癌症。然而，我们现在已经确定 Tim 3不仅在T细胞上表达，而且在髓样细胞和树突状细胞上表达，在这些细胞中，TIM 3抑制 树突状细胞功能和调节抗肿瘤免疫2.在中枢神经系统中，HAVCR 2被鉴定为最重要的免疫调节因子之一。 100个富集的转录物，并在小鼠和人小胶质细胞中特异性表达3 -5，但其作用和 小胶质细胞的功能尚不清楚。 我们的长期目标是确定TIM 3在神经变性中调节小胶质细胞的作用。我们做出了 以下观察：1）Tim 3抑制小胶质细胞活化和吞噬作用：树突状细胞中Tim 3的缺失 细胞促进抗原呈递，我们发现TIM 3也调节小胶质细胞活化和吞噬作用; 2)TGFb-Tim 3轴调节神经退行性变中小胶质细胞表型转换：我们发现TGFb是关键 Tim 3是诱导Tim 3的驱动因子，一旦表达，它就与TGFBR协同作用，增强TGFB信号传导， Tim 3的缺失将M0-稳态小胶质细胞转换为MGnD-非变性表型;以及3）在MGnD-非变性表型中的TIM 3缺失。 小胶质细胞减少5xFAD小鼠中的斑块负荷。这些数据支持遗传连锁研究，并显示 Tim 3在通过调节小胶质细胞功能调节AD疾病病理中的重要性。基于这些 研究中，我们假设TIM 3是小胶质细胞中抑制其反应的关键调节分子， 神经变性、迁移和吞噬功能，从而抑制斑块清除 导致在老化脑中促进Ab沉积、发展和AD进展。基于 这个假设我们提出了三个目标： 目的1：确定TIM 3如何调节5xFAD和P301 S小鼠AD模型的表型和功能。我们 我们建议使用神经元变性和脑tau蛋白病来研究Tim 3的小胶质细胞缺失的作用。 AD小鼠模型。 目的2：TGF β信号通路在小胶质细胞Tim 3表达和功能调控中的作用 发展AD？由于TGF β在维持体内稳态表型中起关键作用， 小胶质细胞，我们建议研究TGF β信号如何诱导Tim 3表达，并促进稳态 通过与TGF β受体信号传导合作来调节小胶质细胞的行为。 目的3：明确TIM 3在AD患者小胶质细胞功能调节中的作用。确定TIM 3 影响人类iPSC衍生的小胶质细胞活化和功能。我们将研究是否遗传或 TIM 3的药理学抑制对表达MGnD的iPSC衍生的人小胶质细胞具有类似的作用 通过利用AD的人源化嵌合小鼠模型用人抗Tim 3抗体治疗表型 总之，靶向小胶质细胞中的TIM 3可能为治疗性调节先天性巨噬细胞凋亡提供一种新的方法。 AD和痴呆症中的免疫。