Identifying New Astrocytic Kir4.1 Channel Modulators for Treating Huntington's Disease

总结 亨廷顿氏病（HD）是一种神经退行性疾病，其特征在于神经系统的进行性损伤， 运动和认知功能，导致不受控制的运动（舞蹈病）、痴呆和寿命缩短 期待亨廷顿蛋白（Htt）的遗传突变是HD的基础，导致细胞内 积聚和聚集，基底神经节广泛神经变性，特别是GABA能 中棘神经元（MSNs）。目前尚无治疗HD的方法。最近的研究集中在 星形胶质细胞在HD中的作用特别是，内向整流钾离子通道Kir4.1下调， HD小鼠纹状体星形胶质细胞，导致MSN神经元过度兴奋。EEAT 2表达和 功能也在HD小鼠中受损。我们假设选择性小分子Kir4.1激活剂可以 增强内源性Kir4.1活性，并可能导致HD的新治疗。为了解决这个问题，我们 建议（1）使用创新方法鉴定Kir4.1通道的新小分子药效团 Kir4.1通道中的虚拟筛选和独特的调节位点，以及（2）评估这些小的 分子Kir4.1药效团对星形胶质细胞-神经元功能和HD小鼠的影响。这些实验将 为探索Kir4.1在HD中的作用的新研究提供基础。

Summary Huntington's Disease (HD) is a neurodegenerative disease that is characterized by progressive impairments of motor and cognitive functions, leading to uncontrolled movements (chorea), dementia and reduced life expectancy. An inherited mutation in the Huntington protein (Htt) underlies HD, leading to intracellular accumulation and aggregation, with extensive neurodegeneration in the basal ganglia, specifically GABAergic medium spiny neurons (MSNs). There are currently no treatments for HD. Recent studies have focused on the role of astrocytes in HD. In particular, the inwardly-rectifying potassium channel Kir4.1 is downregulated in striatal astrocytes of mice with HD, leading to hyperexcitability of MSN neurons. EEAT2 expression and function are also impaired in HD mice. We hypothesize that a selective small molecule Kir4.1 activator could enhance endogenous Kir4.1 activity, and potentially lead to a novel treatment for HD. To address this, we propose to (1) identify new small molecule pharmacophores of Kir4.1 channels using an innovative approach of virtual screening and unique modulatory sites in Kir4.1 channels, and (2) assess the effect of these small molecule Kir4.1 pharmacophores on an astrocytic-neuronal function and HD mice. These experiments will provide the foundation for new studies probing the role of Kir4.1 in HD.