Investigating the neuroinflammatory role of RIP1 kinase

研究 RIP1 激酶的神经炎症作用

• 批准号: 8848334
• 负责人: JUNYING YUAN
• 金额: $ 33.71万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848334
• 关键词: APP-PS1; Adverse effects; Affinity; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Anti-Inflammatory Agents; Anti-Tumor Necrosis Factor Therapy; Anti-inflammatory; Antibodies; Arthritis; Aspirin; Attention; Behavior; Binding; Brain; Cardiovascular system; Caspase Inhibitor; Cell Death; Cells; Cerebrospinal Fluid; Cerebrum; Cessation of life; Chronic; Clinical Research; Clinical Trials; Collection; Data; Death Domain; Dementia; Deposition; Disease; Elderly; Encephalitis; Epidemiologic Studies; Etanercept; Event; FDA approved; Functional disorder; Gene Expression; Genetic; Goals; Health; Human; Immune; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Knowledge; Late Onset Alzheimer Disease; Mediating; Mediator of activation protein; Memory; Microglia; Molecular; Molecular Profiling; Molecular Target; Mus; Network-based; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Onset of illness; Oral; Oral Administration; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Phosphotransferases; Pilot Projects; Play; Process; Production; Reaction; Relative (related person); Reporting; Risk; Role; Safety; Senile Plaques; Signal Pathway; Signal Transduction; Spinal; System; TNF gene; TNFRSF1A gene; Testing; Transgenic Mice; Tryptophan 2,3 Dioxygenase; Tumor Necrosis Factor Receptor; aged; base; cognitive function; cost; cytokine; disorder control; improved; in vivo; inhibitor/antagonist; macrophage; mild cognitive impairment; mouse model; neuron loss; receptor; response; small molecule; tau phosphorylation

DESCRIPTION (provided by applicant): The goal of this proposal is to validate the role and explore the molecular mechanism of RIP1 kinase as a mediator of inflammatory response in Alzheimer's disease (AD), a devastating neurodegenerative disorder and the leading cause of dementia of the elderly. Chronic brain inflammation, characterized by the presence of an increased number of microglia and elevated levels of proinflammatory cytokines, is a hallmark of AD. Increased levels of cerebral spinal TNF? were found in patients with mild cognitive impairment (MCI) at risk to develop AD, suggesting that CNS inflammation is an early event during the pathogenesis of AD. The role of inflammation in the pathogenesis of AD was further highlighted by a recent network-based integrative analysis of a large collection of gene expression profiles from patients of late-onset Alzheimer's disease (LOAD) which discovered the immune/microglia system, including multiple TLR receptors and TNF?, as the molecular system most strongly associated with the pathophysiology of the LOAD. When activated, microglia may release proinflammatory cytokines to drive the chronic progression of AD by exacerbating A? deposition and neuronal death. Identification of the molecular targets in microglia that can be safely modulated to inhibit their inflammatory response may provide new options for the treatment of AD. However, there is a lack of knowledge about the neuroinflammatory mechanism that can be specifically and effectively modulated. We have developed a highly specific and potent inhibitor of RIP1 kinase, 7-Cl-O-Nec-1, a small molecule with excellent oral availability and safety profile, and highly CNS permeable. RIP1 kinase, a death- domain containing Ser/Thr kinase, has an established role in mediating multiple downstream signaling pathways downstream of TNFR1. We found that RIP1 kinase also plays an important role in mediating the production of TNF? by microglia induced by A? in vitro and in PSAPP transgenic mice in vivo which can be effectively inhibited by 7-Cl-O-Nec-1. Furthermore, oral administration of 7-Cl-O-Nec-1 led to the reduction of amyloid plaques and improved behavior and memory of B6.Cg-Tg(APPswe, PSEN1dE9) 85Dbo/J mice (PSAPP) mice, a model for AD. Our study suggests that RIP1 kinase is an important target for inhibiting neuroinflammatory response in AD. This proposal is to test this hypothesis and investigate the mechanism by which RIP1 kinase mediates neuroinflammatory responses in microglia. Specific Aim 1: Investigating the role and mechanism by which RIP1 kinase mediates inflammatory response in microglia activated by oligomeric A? by testing the possible involvement of MKK7 and TLR signaling as downstream mediators of RIP1 signaling. Specific Aim 2: Investigating the role and mechanism of p62 in A? mediated RIP1 kinase activation in microglia by testing the hypothesis that oligomerized p62 provides a platform for mediating RIP1 activation. Specific Aim 3: Genetic confirmation of the role of RIP1 kinase in mediating inflammatory response in AD transgenic mice using a RIP1 kinase dead knockin mouse line.

描述（由申请人提供）：该提案的目的是验证RIP1激酶作为阿尔茨海默氏病炎症反应的介体（AD），毁灭性神经退行性疾病和老年人痴呆症的主要原因。慢性脑炎症的特征是，小胶质细胞数量增加和促炎细胞因子的水平升高，是AD的标志。脑脊髓TNF水平增加？在患有AD的风险的轻度认知障碍（MCI）患者中发现，这表明CNS炎症是AD发病机理期间的早期事件。最近基于网络的集成分析对炎症在AD发病机理中的作用进一步强调了来自阿尔茨海默氏病（负载）患者的大量基因表达谱分析（负载），该疾病发现了免疫/小胶质细胞系统，包括多个TLR受体和TNF？激活后，小胶质细胞可能会释放促炎细胞因子来通过加重A来驱动AD的慢性进展？沉积和神经元死亡。可以安全调节以抑制其炎症反应的小胶质细胞中分子靶标的鉴定可以为AD治疗提供新的选择。但是，缺乏有关神经炎症机制的知识，可以专门和有效地调节。 我们已经开发了一种高度特异性且有效的RIP1激酶，7-CL-O-NEC-1，这是一种具有出色口服可用性和安全性的小分子，并且高度可渗透CNS。 RIP1激酶是一种含有SER/THR激酶的死亡结构域，在介导TNFR1下游的多个下游信号通路中具有确定的作用。我们发现RIP1激酶在介导TNF的产生中也起着重要作用？由A诱导的小胶质细胞？体内和PSAPP转基因小鼠体内可以有效抑制7-CL-O-NEC-1。此外，口服7-CL-O-NEC-1导致淀粉样蛋白斑的减少，改善了B6.CG-TG的行为和记忆（AppSwe，PSEN1DE9）85DBO/J小鼠（PSAPP）小鼠（PSAPP）小鼠，AD的模型。我们的研究表明，RIP1激酶是抑制AD中神经炎症反应的重要靶标。该建议是检验该假设并研究RIP1激酶介导小胶质细胞中神经炎症反应的机制。具体目标1：研究RIP1激酶在低聚A激活的小胶质细胞中介导炎症反应的作用和机制？通过测试MKK7和TLR信号传导作为RIP1信号传导的下游介体的可能参与。特定目标2：研究p62在A中的作用和机制？通过测试寡聚化p62的假设为介导RIP1激活提供了一个平台，从而在小胶质细胞中介导的RIP1激酶激活。具体目标3：使用RIP1激酶死敲蛋白小鼠系列RIP1激酶在AD转基因小鼠中介导炎症反应中的作用的遗传证实。