Neuronal nicotinic receptor modulation and cerebellar ataxias

描述（由申请人提供）：目前没有药物治疗可以缓解共济失调患者表现出的不平衡和随意肌协调缺乏。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，通常可归因于小脑或其相关传入或传出通路的功能丧失。虽然对几种小脑共济失调的遗传基础的了解正在快速增长，并可能导致基因治疗方法的治疗，但这一领域尚处于起步阶段。此外，由于许多共济失调是小脑损伤的结果，不涉及基因改变，因此需要开发治疗药物来减轻与这些疾病相关的症状。临床研究表明，varenicline作为a4b2的部分激动剂和a7神经元烟碱受体的完全激动剂，可以改善不同病因性失调性患者的平衡和协调，并且我们实验室最近的临床前研究已经提供了原理证明，神经元烟碱受体激动剂可以预防脑小脑变性动物模型的进展和/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减轻共济失调的能力，并确定所涉及的细胞机制。需要验证的总体假设是，小脑或下橄榄中a4b2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，从而改变促凋亡和抗凋亡信号之间的平衡，有利于后者。通过一系列补充和平行的体内和体外研究，包括不同的动物模型和基于组织和细胞的分析，本转化提案将使用经典的药理学方法来确定介导神经元烟碱受体激动剂抗共济失调作用的特定受体亚型，并确定这些化合物是否可以缓解由不同化学和遗传损伤引起的共济失调。此外，通过测量参与凋亡信号传导的关键分子，研究将确定尼古丁受体激动剂是否促进细胞存活，以及这种作用是否是尼古丁受体介导的IGF-1表达增加的结果。结果将导致新的治疗药物的发展，目前还没有有效的药物治疗这些疾病。

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.