Treatment of Demyelinating Disease with HSP90 Inhibitors

描述(申请人提供)：脱髓鞘自身免疫性疾病实验性自身免疫性脑脊髓炎(EAE)是研究多发性硬化症(MS)可能病因和治疗干预措施的常用动物模型，涉及T细胞激活、迁移到CMS、诱导实质细胞炎症基因表达、少突胶质细胞损伤和髓鞘丢失，最终导致不可逆转的轴突损伤。炎症基因表达所需的关键信号事件之一是激活转录因子，如胶质细胞和T细胞中的NFkB，以及T细胞中的其他转录因子，如转录因子NFAT。因此，降低转录因子活性的抗炎药可能对治疗有益。我们和其他人已经证明，诱导热休克反应(HSR)可以有效地减少脑胶质细胞中转录因子NFkB的激活和炎症基因的表达，并且完成短暂的高温(42℃，20分钟)可以防止小鼠EAE的发生和发展。也可以通过抑制HSP90蛋白的活性来诱导HSR。抑制HSP90有两个主要后果：释放转录因子HSF1，进而激活HSR；释放和降解“客户”蛋白，其中一些可以增强炎症反应或提高炎症细胞的存活率，如蛋白激酶AKT。在目前的提案中，我们将表征新型小分子HSP90抑制剂在减少神经胶质细胞(星形胶质细胞和小胶质细胞)和T细胞激活以及减缓EAE的临床和病理进展方面的有效性，最终目标是确定用于MS患者进一步测试的化合物。这一目标将通过三个具体目标来实现：目标1，确定HSP90抑制剂阻断神经胶质细胞炎症的能力和机制；目标2，确定HSP90抑制剂阻断T细胞激活的有效性和机制；目标3，使用选定的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 .