Targeting physiologic changes as a route towards therapy for degenerative ataxias

描述(申请人提供)：在大多数遗传性退行性共济失调中，某些类型的神经元的选择性丢失主要发生在小脑和脑干，尽管疾病蛋白广泛表达。许多这些选择性脆弱的神经元表现出自主的起搏器放电。在共济失调中，神经元功能障碍必须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得到很好的证实。我在多谷氨酰胺疾病脊髓小脑性共济失调3型(SCA3)小鼠模型中的初步研究发现，一类起搏神经元-小脑浦肯野神经元的放电特性发生了变化，并表明用钾通道激活剂瞬时纠正这种异常生理可以改善SCA3小鼠的运动表型。这里提出的研究将利用我在电生理学方面的专业知识，并将在SCA3领先的实验室进行，将测试在SCA3中观察到的选择性神经元脆弱性，可能还有其他聚谷氨酰胺共济失调，反映了神经元表达的钾通道特性的变化的假设。该提案有三个目标。目的1研究SCA3区不同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观察到的放电特性的变化。目的2将确定聚谷氨酰胺病蛋白引起钾通道生物物理学改变的机制。目的3研究钾通道生理学调节剂是否能改善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这些目前无法治愈的疾病的对症或预防性治疗的有希望的靶点。这些研究的影响将是将退行性共济失调的领域从主要关注脑形态和生化变化的领域，转向研究神经元功能的特定的、早期的和潜在的可改变的变化。我未来五年的职业目标是成为一名独立的研究人员，具备研究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治疗这些目前无法治愈的疾病的途径的药理学药物。我的长期目标是在一家主要机构的神经科获得并成功获得终身教职，将运动障碍患者的护理结合起来，并领导一个研究实验室，继续询问离子通道在退行性共济失调发病机制中的作用。

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.