Neuronal nicotinic receptor modulation and cerebellar ataxias

描述(申请人提供)：目前还没有药物治疗来缓解共济失调患者表现出的不平衡和缺乏自主肌肉协调。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，通常可归因于小脑或其相关的传入或传出通路的功能丧失。尽管对几种小脑性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出现，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，并不涉及基因改变，因此需要开发治疗药物来缓解与这些疾病相关的症状。临床研究表明，Varenicline是A4b2的部分激动剂和A7神经元尼古丁受体的完全激动剂，可以改善不同病因的共济失调患者的平衡和协调性，最近我们实验室的临床前研究提供了神经元尼古丁受体激动剂预防和/或改善橄榄小脑变性动物模型的运动行为的原理证据。基于这些发现，这项建议的总体目标是进一步表征神经性尼古丁受体激动剂缓解动物模型共济失调的能力，并确定相关的细胞机制。有待检验的总体假设是，小脑或下橄榄中A4b2部分激活和/或A7神经元尼古丁受体完全激活导致细胞环境中胰岛素样生长因子(IGF-1)表达和释放增加，从而使促凋亡和抗凋亡信号之间的平衡向后者倾斜。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，这一翻译建议将使用经典药理学方法来识别介导神经性尼古丁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。结果将导致开发新的治疗药物来治疗这些目前尚无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.