Deletion of Mitochondrial Anchoring Protects Late Phase Multiple Sclerosis

项目摘要 人类MS是一种双相脱髓鞘疾病：存在初始复发-缓解期（RRMS） 其次是第二进展期（SPMS）。SPMS目前无法治愈。审查 在SPMS的病理学方面，我们研究了一种只表现出进行性SPMS的双相小鼠模型（Shiverer）， 相位在R-21（该RO 1的前体）的支持下，我们做出了令人惊讶的发现， SNPH（一种主要的线粒体锚定蛋白）在Shiverer产生显着的神经保护作用。与此相反， 在另一种只表现出RRMS的双相动物模型（EAE/B6）中，删除SNPH没有提供保护作用 相位我们假设SNPH在人类MS中具有双相作用（它在RRMS中有益，在RRMS中有害）。 SPMS）和抑制SNPH SPMS是一种新的治疗进展型MS。 结果在机械（目标1）和平移（目标2和3）方向。 在机制目标1中，我们将研究SNPH-KO如何在体外通过两个- 激活神经保护性线粒体自噬和线粒体融合途径的作用。翻译目的 2，我们将在一种新的双相小鼠模型（EAE/NOD）中表征SNPH病理学， 在表达RRMS和SPMS相两者中的双相模型以更好地模拟人双相MS。 这一补助金的高潮是翻译目标3。我们将在双相治疗中为SPMS阶段设计一种治疗方法。 小鼠模型作为人类进行性MS的可能的未来治疗。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策略来证明治疗的最佳时机是在 当SNPH停止有益并开始变得有害时，从RRMS到SPMS的过渡。二是 组合疗法我们将研究联合治疗（SNPH-KO和抗炎） 可以完全根除双相小鼠模型的进行性阶段中的神经变性。 结论：该项目为当前的治疗设计制定了一个全新的框架 通过双相SNPH假说，我们确定了一个关键的线粒体锚定 在MS进展期间功能从有益转变为有害的蛋白质。这项资助的关键是 目的是验证双相小鼠模型模拟双相人类MS，然后通过靶向SNPH治疗小鼠， 晚期阶段使用条件和组合策略作为治疗人类进行性MS的未来步骤。

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.