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

鉴定用于治疗亨廷顿病的新型星形细胞 Kir4.1 通道调节剂

基本信息

批准号：
10681097
负责人：
Avner Schlessinger
金额：
$ 25.35万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681097
关键词：
Address Affinity Alcohols Amino Acids Antipsychotic Agents Astrocytes Attention Basal Ganglia Biological Assay Brain CAG repeat Cell physiology Cell-Free System Cells Cessation of life Chorea Coculture Techniques Collaborations Corpus striatum structure Delusions Dementia Disease model Electrophysiology (science)Evaluation Excision Foundations Glutamates Goals Grant Hallucinations Hereditary Disease Homeostasis Huntington Disease Huntington gene Impaired cognition Impairment In Vitro Inherited Life Expectancy Ligands Liposomes Movement Mus Mutation National Center for Advancing Translational Sciences Nerve Degeneration Neurodegenerative Disorders Neurons Pathology Play Porifera Potassium Potassium Channel Procedures Research Personnel Role Site Structural Models Synapses Testing Tetrabenazine Toxic effect Transfection Up-Regulation cognitive function experimental study extracellular improved in vivo inhibitor innovation inward rectifier potassium channel motor behavior motor disorder motor impairment mutant neuronal circuitry neuronal excitability neurotransmission novel overexpression pharmacophore polyglutamine protein reconstitution screening sensor small molecule success uptake virtual screening

Address Affinity Alcohols Amino Acids Antipsychotic Agents Astrocytes Attention Basal Ganglia Biological Assay Brain CAG repeat Cell physiology Cell-Free System Cells Cessation of life Chorea Coculture Techniques Collaborations Corpus striatum structure Delusions Dementia Disease model Electrophysiology (science)Evaluation Excision Foundations Glutamates Goals Grant Hallucinations Hereditary Disease Homeostasis Huntington Disease Huntington gene Impaired cognition Impairment In Vitro Inherited Life Expectancy Ligands Liposomes Movement Mus Mutation National Center for Advancing Translational Sciences Nerve Degeneration Neurodegenerative Disorders Neurons Pathology Play Porifera Potassium Potassium Channel Procedures Research Personnel Role Site Structural Models Synapses Testing Tetrabenazine Toxic effect Transfection Up-Regulation cognitive function experimental study extracellular improved in vivo inhibitor innovation inward rectifier potassium channel motor behavior motor disorder motor impairment mutant neuronal circuitry neuronal excitability neurotransmission novel overexpression pharmacophore polyglutamine protein reconstitution screening sensor small molecule success uptake virtual screening

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项目摘要

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.

概括亨廷顿氏病（HD）是一种神经退行性疾病，其特征是电机和认知功能，导致不受控制的运动（唱片），痴呆症和寿命降低期待。亨廷顿蛋白（HTT）中的遗传突变是高清的基础，导致细胞内累积和聚集，基底神经节中具有广泛的神经变性，特别是GABA能中刺神经元（MSN）。目前尚无HD治疗。最近的研究重点是星形胶质细胞在高清中的作用。特别是，内部切除的钾通道Kir4.1在下调具有HD的小鼠的纹状体星形胶质细胞，导致MSN神经元过度兴奋。 EEAT2表达和 HD小鼠的功能也受损。我们假设选择性的小分子kir4.1激活剂可以增强内源性KIR4.1活性，并有可能导致对HD的新型治疗。为了解决这个问题，我们提议（1）使用创新方法来识别KIR4.1通道的新小分子药算术 Kir4.1频道中的虚拟筛选和独特的调节位点，（2）评估这些小的效果分子KIR4.1药剂归因于星形细胞神经元功能和HD小鼠。这些实验会为探测Kir4.1在HD中的作用的新研究提供基础。