Validation of IKKbeta as a therapeutic target for HD

验证 IKKbeta 作为 HD 治疗靶点

• 批准号: 8697149
• 负责人: Ali Khoshnan
• 金额: $ 35.52万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697149
• 关键词: Affect; Animal Model; Biological Assay; Biology; Blood - brain barrier anatomy; Brain; Brain region; CAG repeat; Caspase; Collaborations; Corpus striatum structure; Cues; Cultured Cells; DNA Damage; Data; Development; Disease; Disease Progression; Environmental Risk Factor; Evaluation; Event; Exhibits; Exons; Generations; Genetic; Human; Huntington Disease; Inflammation Mediators; Inflammatory; Inflammatory Response; Inherited; Interleukin-6; Knock-in Mouse; Laboratories; Lead; Mediating; Mediator of activation protein; Microglia; Mitotic; Modeling; Modification; Motor; Mus; N-terminal; NFKB Signaling Pathway; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathology; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Production; Research Personnel; Role; Serum; Signal Pathway; Slice; Symptoms; Testing; Therapeutic; Validation; age related; age related neuroinflammation; base; caspase-6; chemical genetics; cytokine; efficacy testing; human Huntingtin protein; in vitro testing; in vivo; inflammatory marker; inhibitor/antagonist; kinase inhibitor; mimetics; mouse model; mutant; neuroinflammation; neurotoxic; neurotoxicity; new therapeutic target; novel therapeutics; offspring; prevent; small molecule; success; therapeutic target

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an autosomally inherited neurodegenerative disorder that is caused by expansion of CAG repeats in exon-1 of huntingtin (Htt). Enzymatic cleavage of mutant Htt protein leads to the generation of neurotoxic, amyloidogenic fragments and is one of the earliest events in HD pathogenesis. The environmental cues and the signaling pathways that regulate Htt cleavage are poorly understood, however. HD is an age-dependent disorder and age-related factors such as the accumulation of DNA damage and neuroinflammation are likely to influence its progression. The IkB kinase (IKK)/NF-kB signaling pathway is activated by these environmental factors and is implicated in the pathogenesis of HD. IKK? is responsive to DNA damage and mediates inflammatory responses. Our results demonstrate that pre- symptomatic HD mice have elevated IKK? activity localized to the striatum, while symptomatic HD mice also exhibit elevated IKK? activity in other brain regions including cortex. Inhibition of IKK? reduces the neurotoxicity of amyloidogenic fragments of Htt in a brain slice culture model of HD. We also find that IKK? activation induced by DNA damage promotes caspase-dependent WT and mutant Htt cleavage in post-mitotic human neurons. Genetic and chemical inhibition of IKK? prevents caspase activation and Htt cleavage, while increasing neuronal resiliency to DNA damage. Recent studies implicate IKK? in the phosphorylation of N-terminus (Ser13 and Ser16) of Htt. Phospho- mimetic modification of these residues ameliorates disease in HD mice. Preliminary studies from our laboratory and other investigators indicate that IKK? inhibition promotes the phosphorylation of Htt in neuronal models. Thus, IKK? is a key regulator of HD pathogenesis and its inhibition may be protective in HD. Moreover, deregulated IKK? is likely responsible for neuroinflammation, which occurs years before the onset of motor symptoms in patients. We propose to investigate the role of IKK? in HD pathogenesis in several animal models. We will delete IKK? in the brains of HD mice and examine whether the lack of IKK? prevents Htt cleavage, neuroinflammation and thereby ameliorates pathology. Furthermore, we plan to test the efficacy of small molecule inhibitors of IKK? as potentially novel therapeutics for HD.

描述（由申请人提供）：亨廷顿氏病（HD）是一种遗传遗传的神经退行性疾病，是由Huntingtin（HTT）外显子1中CAG重复序列扩展引起的。突变HTT蛋白的酶促切割导致神经毒性，淀粉样蛋白生成片段的产生，并且是HD发病机理中最早的事件之一。但是，对调节HTT裂解的环境提示和信号通路知之甚少。 HD是一种依赖年龄的疾病，与年龄相关的因素，例如DNA损伤和神经炎症的积累可能会影响其进展。 IKB激酶（IKK）/NF-KB信号通路被这些环境因素激活，并与HD的发病机理有关。 ikk？对DNA损伤有反应并介导炎症反应。我们的结果表明，症状前HD小鼠IKK升高了？位于纹状体的活动，而有症状的HD小鼠也表现出升高的IKK？包括皮质在内的其他大脑区域的活动。抑制IKK？在HD的脑切片培养模型中，降低了HTT的淀粉样蛋白生成片段的神经毒性。我们还发现IKK吗？由DNA损伤诱导的激活促进了caspase依赖性WT和突变的HTT裂解后有丝分裂后人类神经元中的裂解。 IKK的遗传和化学抑制？防止胱天蛋白酶激活和HTT裂解，同时提高神经元弹性对DNA损伤。最近的研究暗示了IKK？在HTT的N末端（Ser13和Ser16）的磷酸化中。这些残基的磷酸化修饰可改善HD小鼠的疾病。我们实验室和其他研究人员的初步研究表明IKK？抑制促进了神经元模型中HTT的磷酸化。因此，IKK？是HD发病机理的关键调节剂，其抑制作用可能在HD中具有保护性。而且，放松管制的IKK？可能导致神经炎症，这发生在患者运动症状发作之前的几年。我们建议调查IKK的作用？在几种动物模型中的HD发病机理中。我们会删除IKK吗？在高清小鼠的大脑中，检查是否缺乏IKK？防止HTT裂解，神经炎症，从而改善病理。此外，我们计划测试IKK小分子抑制剂的功效？作为HD的潜在新型治疗剂。