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（申请人提供）：亨廷顿病（HD）是一种常染色体遗传性神经退行性疾病，由亨廷顿蛋白（Htt）外显子1中CAG重复序列扩增引起。突变型Htt蛋白的酶裂解导致神经毒性的淀粉样蛋白片段的产生，并且是HD发病机制中最早的事件之一。然而，对调节Htt裂解的环境信号和信号通路知之甚少。HD是一种年龄依赖性疾病，年龄相关因素如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，并参与HD的发病机制。IKK？对DNA损伤有反应并介导炎症反应。我们的研究结果表明，症状前HD小鼠IKK？活动定位于纹状体，而症状性HD小鼠也表现出IKK升高？包括皮层在内的其他脑区的活动。抑制IKK？降低HD脑切片培养模型中Htt的淀粉样蛋白生成片段的神经毒性。我们还发现IKK？在有丝分裂后的人神经元中，DNA损伤诱导的活化促进半胱天冬酶依赖性WT和突变型Htt裂解。IKK的遗传和化学抑制？防止半胱天冬酶活化和Htt裂解，同时增加神经元对DNA损伤的弹性。最近的研究表明IKK？在Htt的N端（Ser 13和Ser 16）的磷酸化中。这些残基的拟磷酸修饰改善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？抑制促进神经元模型中Htt的磷酸化。因此，IKK？是HD发病机制的关键调节因子，其抑制可能在HD中具有保护作用。此外，解除管制的IKK？可能是神经炎症的原因，神经炎症发生在患者运动症状发作前数年。我们建议调查IKK的作用？在HD发病机制中的作用。我们将删除IKK？在HD小鼠的大脑，并检查是否缺乏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的小分子抑制剂的疗效？作为HD的潜在新疗法。