Neuronal nicotinic receptor modulation and cerebellar ataxias

描述（由申请人提供）：目前尚无药物治疗来缓解共济失调患者表现出的不平衡和缺乏随意肌肉协调。影响平衡和协调的共济失调运动可能是遗传性疾病或非遗传性原因的结果，并且通常可能归因于小脑或其相关传入或传出通路的功能丧失。尽管对几种小脑共济失调的遗传基础的了解正在迅速增加，并可能导致基因治疗方法的治疗，但这一领域仍处于起步阶段。此外，由于许多共济失调是小脑损伤的结果，并且不涉及遗传改变，因此需要开发治疗剂以减轻与这些病症相关的症状。临床研究表明，varenicline，一种a4 b2的部分激动剂和a7神经元烟碱受体的完全激动剂，改善了具有不同致病病因学的共济失调患者的平衡和协调，并且我们实验室最近的临床前研究提供了原理证明，即神经元烟碱受体激动剂在橄榄小脑变性的动物模型中预防运动行为的进展和/或改善运动行为。基于这些发现，本提案的总体目标是进一步表征神经元烟碱受体激动剂在动物模型中缓解共济失调的能力，并确定所涉及的细胞机制。待测试的总体假设是小脑或下橄榄中a4 b2的部分激活和/或a7神经元烟碱受体的完全激活导致细胞环境中胰岛素样生长因子（IGF-1）的表达和释放增加，这改变了促凋亡和抗凋亡信号传导之间的平衡以有利于后者。通过一个互补的和平行的一系列的体内和体外研究，涉及不同的动物模型和组织和细胞为基础的测定，这种翻译建议将使用一个经典的药理学方法，以确定特定的受体亚型介导的神经元烟碱受体激动剂的抗共济失调作用，并确定这些化合物是否可以减轻共济失调导致不同的化学和遗传的侮辱。此外，通过测量参与凋亡信号传导的关键分子，研究将确定烟碱受体激动剂是否促进细胞存活，以及这种作用是否是烟碱受体介导的IGF-1表达增加的结果。结果将导致开发新的治疗药物来治疗这些目前没有有效药物治疗的疾病。

DESCRIPTION (provided by applicant): There is no current pharmacological treatment to alleviate the imbalance and lack of voluntary muscle coordination manifest by individuals with ataxia. Ataxic movements affecting balance and coordination may be a consequence of either hereditary diseases or non-hereditary causes, and typically may be ascribed to a loss of function in the cerebellum or its associated afferent or efferent pathways. Although knowledge of the genetic basis of several cerebellar ataxias is increasing at a rapid pace and may lead to gene therapy approaches for treatment, this area is in its infancy. In addition, because many ataxias are a consequence of a cerebellar insult and do not involve genetic alterations, there is a need for the development of therapeutic agents to alleviate the symptoms associated with these disorders. Clinical studies have indicated that varenicline, a partial agonist at a4b2 and full agonist at a7 neuronal nicotinic receptors, improves balance and coordination in patients with ataxias of distinct pathogenic etiology, and recent preclinical studies in our laboratory have provided proof-of-principle that neuronal nicotinic receptor agonists prevent the progression of and/or improve motor behavior in an animal model of olivocerebellar degeneration. Based on these findings, the overall goal of this proposal is to further characterize the ability of neuronal nicotinic receptor agonists to alleviate ataxia in animal models and identify the cellular mechanisms involved. The overall hypothesis to be tested is that the partial activation of a4b2 and/or full activation of a7 neuronal nicotinic receptors in the cerebellum or inferior olive leads to the increased expression and release of insulin-like growth factor (IGF-1) in the cellular milieu, which shifts the balance between pro-apoptotic and anti-apoptotic signaling to favor the latter. Through a complementary and parallel series of in vivo and in vitro studies involving both diverse animal models and tissue and cell-based assays, this translational proposal will use a classical pharmacological approach to identify the specific receptor subtypes mediating the anti-ataxic effects of neuronal nicotinic receptor agonists and determine whether these compounds can alleviate ataxias resulting from different chemical and genetic insults. Further, through measures of key molecules involved in apoptotic signaling, studies will ascertain whether nicotinic receptor agonists promote cell survival, and whether this action is a consequence of a nicotinic receptor-mediated increased expression of IGF-1. Results will lead to the development of new therapeutic agents for the treatment of these disorders for which there is no current efficacious pharmacological therapy.