Targeting physiologic changes as a route towards therapy for degenerative ataxias

描述（由申请人提供）：在大多数遗传性退行性共济失调中，尽管疾病蛋白广泛表达，但某些类型的神经元的选择性丧失主要发生在小脑和脑干中。许多这些选择性脆弱的神经元表现出自主起搏器放电。共济失调中神经元功能障碍必然先于神经元的最终丧失，但这种神经元功能障碍的性质及其与运动症状的因果关系尚未完全确定。我的初步研究在小鼠模型的多聚谷氨酰胺疾病脊髓小脑共济失调3型（SCA3）已经确定了改变放电特性的一类起搏神经元，小脑浦肯野神经元，并已表明，暂时纠正这种异常的生理与钾通道激活剂改善运动表型SCA3小鼠。 这里提出的研究，利用我在电生理学方面的专业知识，并将在一个领先的SCA3实验室进行，将测试的假设，即选择性神经元的脆弱性SCA3中观察到的，并可能其他多聚谷氨酰胺共济失调，反映了神经元表达的钾通道的特性的改变。该提案有三个目标。目的1将检查SCA3中各种受影响的起搏神经元的放电特性，并确定钾通道生理学的改变是否可以解释所观察到的放电特性变化。目的2探讨多聚谷氨酰胺病蛋白引起钾通道生物物理变化的机制。目的3将检测钾通道生理学调节剂是否可以改善SCA3小鼠的运动症状。这些研究的总体目标是确定这些生理变化是否是对症或预防治疗这些目前无法治疗的疾病的有希望的目标。这些研究的影响将是将退行性共济失调的领域，主要集中在脑形态和生物化学的变化，朝着寻找特定的，早期的和潜在的可修改的神经元功能的变化。 我在未来五年的职业目标是成为一名独立的研究人员，拥有调查SCA3和相关共济失调的生理基础的专业知识，并设计和测试可以作为这些目前无法治疗的疾病的治疗途径的药理学药物。我的长期目标是在一家大型机构的神经病学部门获得终身教职并取得成功，将运动障碍患者的护理与领导一个研究实验室相结合，继续询问离子通道在退行性共济失调疾病发病机制中的作用。 公共卫生相关性：脊髓小脑性共济失调3型（SCA3）是共济失调的最常见的显性遗传形式，其导致患者失去平衡和协调，并且与某些脑区域（特别是小脑和脑干）中的神经细胞损失相关。该提案研究了纠正SCA3中这些受影响大脑区域神经细胞电特性的扰动是否会导致新药的开发，以治疗这种目前无法治疗的致命疾病。

DESCRIPTION (provided by applicant): In most inherited degenerative ataxias, selective loss of certain types of neurons occurs primarily in the cerebellum and brain stem despite widespread expression of the disease protein. Many of these selectively vulnerable neurons exhibit autonomous pacemaker firing. Neuronal dysfunction must precede the eventual loss of neurons in ataxia, but the nature of this neuronal dysfunction and its causal relationship to motor symptoms are not well established. My preliminary studies in a mouse model of the polyglutamine disorder Spinocerebellar Ataxia Type 3 (SCA3) have identified altered firing properties of one class of pacemaker neurons, the cerebellar Purkinje neurons, and have shown that transiently correcting this aberrant physiology with a potassium channel activator improves the motor phenotype in SCA3 mice. The studies proposed here, which take advantage of my expertise in electrophysiology and will be performed in a leading SCA3 laboratory, will test the hypothesis that the selective neuronal vulnerability observed in SCA3, and possibly other polyglutamine ataxias, reflects alterations in the properties of neuronally expressed potassium channels. The proposal has 3 aims. Aim 1 will examine the firing properties of various affected pacemaker neurons in SCA3 and determine whether alterations in potassium channel physiology can explain the observed changes in firing properties. Aim 2 will determine the mechanism for polyglutamine disease protein-induced changes in potassium channel biophysics. Aim 3 will examine whether modulators of potassium channel physiology can improve the motor symptoms in SCA3 mice. The overall objective of these studies is to determine whether such physiologic changes are promising targets for symptomatic or preventive treatment of these currently untreatable disorders. The impact of these studies will be to move the field of degenerative ataxias, which has focused primarily on changes in brain morphology and biochemistry, towards looking at specific, early and potentially modifiable changes in neuronal function. My career goal over the next five years is to become an independent researcher with the expertise to investigate the physiologic underpinnings of SCA3 and related ataxias and to design and test pharmacologic agents that can serve as a route to therapy for these currently untreatable disorders. My long term goal is to secure and succeed in a tenure-track faculty position at a neurology department at a major institution, combining the care of patients with movement disorders and heading a research laboratory that continues to interrogate the role of ion-channels in the pathogenesis of degenerative ataxic disorders. PUBLIC HEALTH RELEVANCE: Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited form of ataxia, causes loss of balance and coordination in patients and is associated with a loss of nerve cells in certain brain regions, notably the cerebellum and brain stem. This proposal examines whether correcting perturbations in the electrical properties of nerve cells in these affected brain regions in SCA3 will lead to the development of new drugs to treat this currently untreatable, fatal disorder.