Investigating the neuroinflammatory role of RIP1 kinase

研究 RIP1 激酶的神经炎症作用

• 批准号: 9066393
• 负责人: JUNYING YUAN
• 金额: $ 7.77万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066393
• 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）：本提案的目的是验证 RIP1 激酶作为阿尔茨海默病 (AD) 炎症反应介质的作用并探索其分子机制，阿尔茨海默病是一种破坏性神经退行性疾病，也是导致痴呆的主要原因。老年。慢性脑炎症是 AD 的一个标志，其特征是小胶质细胞数量增加和促炎细胞因子水平升高。脑脊髓TNF水平升高？在有患 AD 风险的轻度认知障碍 (MCI) 患者中发现，表明中枢神经系统炎症是 AD 发病机制中的早期事件。最近对迟发性阿尔茨海默病 (LOAD) 患者的大量基因表达谱进行的基于网络的综合分析进一步强调了炎症在 AD 发病机制中的作用，该分析发现了免疫/小胶质细胞系统，包括多个 TLR受体和 TNF?，作为与 LOAD 病理生理学最密切相关的分子系统。当被激活时，小胶质细胞可能会释放促炎细胞因子，通过加剧 A? 来驱动 AD 的慢性进展。沉积和神经元死亡。鉴定小胶质细胞中可以安全调节以抑制其炎症反应的分子靶点可能为治疗 AD 提供新的选择。然而，对于可以特异性和有效调节的神经炎症机制缺乏了解。 我们开发了一种高度特异性和有效的 RIP1 激酶抑制剂 7-Cl-O-Nec-1，这是一种具有出色的口服利用度和安全性以及中枢神经系统高度渗透性的小分子。 RIP1 激酶是一种包含 Ser/Thr 激酶的死亡结构域，在介导 TNFR1 下游的多个下游信号传导途径中具有确定的作用。我们发现RIP1激酶在介导TNFα的产生中也发挥着重要作用？由A诱导的小胶质细胞？ 7-Cl-O-Nec-1 可以有效抑制体外和 PSAPP 转基因小鼠的体内实验。此外，口服 7-Cl-O-Nec-1 可以减少淀粉样蛋白斑，改善 AD 模型 B6.Cg-Tg(APPswe, PSEN1dE9) 85Dbo/J 小鼠 (PSAPP) 小鼠的行为和记忆力。我们的研究表明 RIP1 激酶是抑制 AD 神经炎症反应的重要靶点。本提案旨在检验这一假设并研究 RIP1 激酶介导小胶质细胞神经炎症反应的机制。具体目标1：研究RIP1激酶介导寡聚A？激活的小胶质细胞炎症反应的作用和机制。通过测试 MKK7 和 TLR 信号传导作为 RIP1 信号传导下游介质的可能参与情况。具体目标2：研究p62在A？通过测试寡聚化 p62 为介导 RIP1 激活提供平台的假设，介导小胶质细胞中的 RIP1 激酶激活。具体目标 3：使用 RIP1 激酶死亡敲入小鼠品系对 RIP1 激酶在 AD 转基因小鼠中介导炎症反应中的作用进行遗传确认。