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，但某些类型神经元的选择性丧失主要发生在小脑和脑干。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不清楚。我对3型脊髓小脑性失调（SCA3）的小鼠模型进行了初步研究，发现一类起搏器神经元（小脑浦肯野神经元）的放电特性发生了改变，并表明用钾通道激活剂暂时纠正这种异常生理可以改善SCA3小鼠的运动表型。这里提出的研究利用了我在电生理学方面的专业知识，将在一个领先的SCA3实验室进行，将测试在SCA3中观察到的选择性神经元易感性，以及可能的其他多谷氨酰胺共济失调，反映了神经元表达钾通道特性的改变。该提案有三个目标。目的1将检查SCA3中各种受影响的起搏器神经元的放电特性，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将确定多聚谷氨酰胺病蛋白诱导钾通道生物物理变化的机制。目的3将研究钾通道生理调节剂是否能改善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有希望对这些目前无法治疗的疾病进行对症或预防性治疗。这些研究的影响将推动退行性共济失调领域的发展，该领域主要关注脑形态和生物化学的变化，转向研究神经元功能中特定的、早期的和潜在的可改变的变化。我在未来五年的职业目标是成为一名独立的研究人员，具有调查SCA3和相关共济失调的生理基础的专业知识，并设计和测试药物，可以作为治疗这些目前无法治疗的疾病的途径。我的长期目标是在一家大型机构的神经内科获得并成功获得终身教职，结合对运动障碍患者的护理，并领导一个研究实验室，继续研究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. 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.