Deletion of Mitochondrial Anchoring Protects Late Phase Multiple Sclerosis

线粒体锚定的缺失可保护晚期多发性硬化症

• 批准号: 9289458
• 负责人: SHING Yan CHIU
• 金额: $ 33.47万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9289458
• 关键词: Animal Model; Axon; Behavior; CRISPR/Cas technology; Cause of Death; Cerebellum; Data; Demyelinating Diseases; Disease; Energy Supply; Exhibits; Experimental Autoimmune Encephalomyelitis; Future; Goals; Grant; Health; Human; In Vitro; Inbred NOD Mice; Inflammation; Investigation; Laboratories; Mediating; Microfluidics; Mitochondria; Modeling; Multiple Sclerosis; Mus; Nerve Degeneration; Nervous system structure; Neurons; Pathologic; Pathology; Pathway interactions; Phase; Process; Proteins; Recycling; Relapse; Role; Running; Sampling; Secondary to; Shivering; System; Testing; Time; Writing; base; clinically relevant; combinatorial; design; insight; mouse model; multiple sclerosis patient; neuron loss; neuronal cell body; neuroprotection; novel; novel therapeutics; prevent; syntaphilin; therapy design

PROJECT SUMMARY Human MS is a biphasic demyelinating disease: there is an initial relapsing-remitting phase (RRMS) followed by a secondary progressive phase (SPMS). The SPMS is currently incurable. To examine the pathology of SPMS, we studied a monophasic mouse model (Shiverer) that exhibits only the progressive phase. Under support of an R-21 (precursor to this RO1), we made the surprising discovery that deleting SNPH (a major mitochondrial anchoring protein) in Shiverer produces dramatic neuroprotection. In contrast, deleting SNPH offers no protection in another monophasic animal model (EAE/B6) that exhibits only the RRMS phase. We hypothesize that SNPH has a biphasic role in human MS (it is beneficial in RRMS and harmful in SPMS) and that inhibiting SNPH in SPMS is a novel therapy for progressive MS. This grant extends the R-21 results in mechanistic (Aim 1) and translational (Aim 2 & 3) directions. In Mechanistic Aim 1, we will examine how SNPH-KO protects pathologic neurons in vitrro by a two- pronged action to activate neuroprotective mitophagy and mitochondrial fusion pathways. In Translational Aim 2, we will characterize SNPH pathology in a novel biphasic mouse model (EAE/NOD) that is superior to our monophasic models in expressing both RRMS and SPMS phases to better mimic human biphasic MS. The climax of this grant is Translational Aim 3. We will design a treatment for the SPMS phase in the biphasic mouse model as a possible future treatment for human progressive MS. Our treatment design is two-fold. First is timing of therapy. We will use conditional SNPH-KO strategy to show that the best timing for treatment is at the transition from RRMS to SPMS when SNPH stops being beneficial and starts becoming harmful. Second is combinatorial therapy. We will examine whether a combinatorial therapy (SNPH-KO and anti-inflammation) might completely eradicate neurodegeneration in the progressive phase of the biphasic mouse model. Conclusion: This project formulates a brand new framework for designing treatments for the currently incurable progressive MS. Through a biphasic SNPH hypothesis, we pinpoint a key mitochondrial anchoring protein whose function switches from being beneficial to harmful during MS progression. The crux of this grant is to validate a biphasic mouse model to mimic biphasic human MS, then treat the mouse by targeting SNPH in the late phase using conditional and combinatorial strategies as a future step to treat human progressive MS.

项目总结 人类多发性硬化是一种双相脱髓鞘疾病：有一个初始复发-缓解期(RRMS) 之后是第二进展阶段(SPMS)。SPMS目前是不治之症。要检查 在SPMS的病理学方面，我们研究了一种单相小鼠模型(寒战)，该模型仅表现出进行性的 相位。在R-21(RO1的前身)的支持下，我们有了一个令人惊讶的发现，删除 颤栗中的SNPH(一种主要的线粒体锚定蛋白)具有显著的神经保护作用。相比之下， 在另一个仅表现RRMS的单相动物模型(EAE/B6)中，删除SNPH并不能提供保护 相位。我们假设SNPH在人类多发性硬化中具有双相作用(在RRMS中有益，在RRMS中有害 在SPMS中抑制SNPH是治疗进展性MS的一种新疗法。这项拨款延长了R-21 结果是机械方向(目标1)和平移方向(目标2和3)。 在机械目标1中，我们将研究SNPH-KO如何通过两种不同的方式保护体外培养的病理性神经元。 激活神经保护性有丝分裂和线粒体融合途径的作用。在翻译目标中 2，我们将在一种新的双相小鼠模型(EAE/NOD)中表征SNPH的病理特征，该模型优于我们的 同时表达RRMS和SPMS相的单相模型，以更好地模拟人类双相MS 这笔赠款的高潮是翻译目标3。我们将设计一种治疗双相SPMS阶段的方法 小鼠模型作为未来可能治疗人类进展性多发性硬化症的一种方法，我们的治疗设计是双重的。第一 是治疗的时机。我们将使用条件SNPH-KO策略来表明治疗的最佳时机是在 当SNPH不再有益而开始变得有害时，从RRMS到SPMS的转变。第二个是 综合疗法。我们将检查联合治疗(SNPH-KO和抗炎)是否 可能完全根除双相小鼠模型进展期的神经退行性变。 结论：本项目为设计治疗方案提供了一个全新的框架。 无法治愈的进展性多发性硬化症通过双相性SNPH假说，我们精确定位了关键的线粒体锚定。 在多发性硬化症进展过程中其功能由有益变为有害的蛋白质。这笔赠款的症结在于 是验证双相小鼠模型以模拟双相人类多发性硬化症，然后通过靶向SNPH来治疗小鼠 晚期使用条件和组合策略作为治疗人类进展性MS的未来步骤。