Treatment of Demyelinating Disease with HSP90 Inhibitors

描述（由申请人提供）：脱髓鞘性自身免疫性疾病实验性自身免疫性脑脊髓炎（EAE）是一种常用的动物模型，用于研究多发性硬化症（MS）的可能原因和治疗干预措施，包括t细胞活化、向CMS迁移、诱导实质细胞炎症基因表达、少突胶质细胞损伤和髓磷脂损失，以及最终不可逆的轴突损伤。炎症基因表达所需的关键信号事件之一是转录因子的激活，如神经胶质细胞和T细胞中的NFkB，以及T细胞中的其他转录因子NFAT。因此，减少转录因子激活的抗炎剂可能具有治疗益处。我们和其他人已经证明，热休克反应（HSR）的诱导可以有效地降低转录因子NFkB的激活和脑胶质细胞中的炎症基因表达，并且短暂的高温（42°C 20分钟）可以阻止小鼠EAE的发生和发展。通过抑制HSP90蛋白的活性也可以诱导HSR。抑制HSP90有两个主要后果：释放转录因子HSF1，进而激活HSR；以及“客户”蛋白的释放和降解，其中一些蛋白可以增强炎症反应或增加炎症细胞的存活，如蛋白激酶AKT。在目前的提案中，我们将表征新型小分子HSP90抑制剂降低胶质细胞（星形胶质细胞和小胶质细胞）和t细胞活化的功效，并减少EAE的临床和病理进展，最终目标是确定化合物以进一步在MS患者中进行测试。这一目标将在三个具体目标中得到解决：目标1，表征HSP90抑制剂阻断胶质细胞炎症的能力和机制；目的2，确定HSP90抑制剂阻断t细胞活化的功效和机制；目的3：选择HSP90抑制剂阻断慢性和复发性EAE模型的临床和组织学症状。

DESCRIPTION (provided by applicant): The demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE) is an often-used animal model to study possible causes and therapeutic interventions for Multiple Sclerosis (MS), which involves T-cell activation, migration into the CMS, induction of parenchymal cell inflammatory gene expression, damage to oligodendrocytes and myelin loss, and eventually irreversible axonal damage. One of the key signaling events required for inflammatory gene expression is activation of transcription factors, such as NFkB in glial cells and T cells, and of other such as transcription factor NFAT in T cells. Anti-inflammatory agents which reduce transcription factor activation could therefore be of therapeutic benefit. We and others have shown that induction of a heat shock response (HSR) potently reduced activation of transcription factor NFkB and inflammatory gene expression in brain glial cells, and that a brief period of hyperthermia (42¿C for 20 minutes) completed prevented the onset and development of EAE in mice. A HSR can also be induced by inhibiting activity of the HSP90 protein. Inhibition of HSP90 has two primary consequences: release of transcription factor HSF1 which in turn activates the HSR; and release and degradation of 'client' proteins, some of which can potentiate inflammatory responses or increase survival of inflammatory cells, such as the protein kinase AKT. In the current proposal, we will characterize the efficacy of novel small molecular weight HSP90 inhibitors to reduce glial (astrocyte and microglial) and T-cell activation, and to reduce clinical and pathological progression in EAE, with the ultimate goal of identifying compounds for further testing in MS patients. This goal will be addressed in 3 specific aims: Aim 1, characterizing the ability and mechanism of HSP90 inhibitors to block glial cell inflammation; Aim 2, determine the efficacy and mechanisms of HSP90 inhibitors to block T-cell activation; Aim 3, use selected HSP90 inhibitors to block clinical and histological symptoms in chronic and relapsing EAE model .