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SK Channel Openers as Therapeutics for Cerebellar Ataxia

SK 通道开放剂作为小脑性共济失调的治疗药物

基本信息

批准号：
7491941
负责人：
HEIKE WULFF
金额：
$ 3.9万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-15 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7491941
关键词：
Abnormal coordination Accounting Amyotrophic Lateral Sclerosis Animal Model Ataxia Causations Cerebellar Ataxia Cerebellum Chloride Channels Clinical Trials Depth Disease Dose Drug Kinetics Effectiveness Evaluation Family Fire - disasters Foundations Frequencies Functional disorder Gait abnormality Glutamates Human Intention Tremor Laboratories Life Mediating Modeling Motor Mus Nerve Degeneration Neurons Other Finding Output Pathway interactions Patients Performance Pharmaceutical Preparations Pharmacotherapy Phenotype Preventive Protein Isoforms Purkinje Cells Reporting Riluzole Role SCA2 protein Sodium Channel Spinocerebellar Ataxias Symptoms Testing Therapeutic Therapeutic Effect Tissues Transgenic Organisms Type 2 Spinocerebellar Ataxia United States Food and Drug Administration cell type concept day design improved mouse model mutant nervous system disorder novel novel therapeutics promoter research study sedative tool treatment duration

项目摘要

Cerebellar ataxia is a lethal neurological disease, which afflicts about 150,000 people in the US. There are currently no known preventive, neuroprotective or symptomatic treatments for this devastating disease. Using a transgenic mouse model we recently identified a novel mechanism of initiation of cerebellar ataxia through hyperexcitability of the deep cerebellar neurons (DCN), the sole output pathway of the cerebellum. Small conductance Ca -activated K+ (SK) channels, key regulators of firing frequency in the DCN, were silenced in DCN neurons of Tg mice with a naturally occurring dominant-inhibitory SK isoform (SK3-1B) that suppresses the entire SK channel family. Tg mice developed severe cerebellar ataxia by the 12th day of life characterized by motor incoordination, intention tremor and gait abnormalities in the absence of neurodegeneration. This model, together with findings from other animal models for cerebellar ataxia, strongly suggests that increased DCN excitability may be an important step in the causation of this disorder. Pharmacological reduction of DCN excitability may provide a novel therapeutic approach for cerebellar ataxia. Since SK channels are critical in regulating the firing frequency of DCN neurons and their blockade causes enhanced firing, an opener of SK channels should slow down DCN firing and ameliorate the symptoms of cerebellar ataxia. Riluzole, a FDA approved drug for the therapy of amyotrophic lateral sclerosis, has been reported to be a potent SK channel opener. In a preliminary study in a Tg mouse model for human spinocerebellar ataxia type 2 (SCA2), we found that riluzole produced a dramatic improvement in motor performance after only 4 days of treatment. We plan to extend these exciting preliminary findings by pursuing three specific aims: Aim 1: Evaluation of riluzole in two animal models of ataxia; Aim 2: Design of a more potent and selective SK opener that unlike riluzole does not block slowly- inactivating sodium channels; Aim 3: Evaluation of our new SK opener in two animal models of ataxia. Taken together these important proof-of-concept studies will help to determine whether SK channel openers constitute a new therapeutic approach to improve motor performance in dominant cerebellar ataxias.

小脑性共济失调是一种致命的神经系统疾病，在美国约有15万人受到影响。确实有目前还没有已知的预防、神经保护或对症治疗方法来治疗这种毁灭性的疾病。利用转基因小鼠模型，我们最近发现了一种新的小脑性共济失调发病机制。通过小脑深部神经元(DCN)的过度兴奋，这是小脑唯一的输出途径。小电导钙激活的K+(SK)通道是DCN放电频率的关键调节因子。在具有自然产生的显性抑制SK亚型(SK3-1B)的TG小鼠DCN神经元中沉默抑制整个SK通道族。转基因小鼠在出生12天时出现严重的小脑性共济失调以运动不协调、意图震颤和步态异常为特征神经退行性变。这一模型，连同其他小脑性共济失调动物模型的研究结果，强烈提示DCN兴奋性的增加可能是导致这种疾病的重要一步。药物降低DCN兴奋性可能为小脑提供一种新的治疗方法共济失调。由于SK通道在调节DCN神经元的放电频率及其阻断中起关键作用导致增强发射，SK频道的开启器应该减缓DCN发射并改善小脑性共济失调的症状。利鲁唑，FDA批准的治疗肌萎缩侧索硬化症的药物据报道，硬化症是一种有效的SK通道开放剂。在TG小鼠模型的初步研究中对于人类脊髓小脑型共济失调2(Sca2)，我们发现利鲁唑在仅治疗4天后运动功能恢复。我们计划通过以下方式扩展这些令人兴奋的初步发现追求三个具体目标：目的1：评价利鲁唑在两种共济失调动物模型中的作用；目标2：设计一种更有效、更有选择性的SK开瓶器，与利鲁唑不同，它不会缓慢堵塞- 使钠通道失活；目的3：在两种共济失调动物模型上评价我们新的SK开放器。综合起来，这些重要的概念验证研究将有助于确定SK渠道开通者为改善显性小脑性共济失调患者的运动能力提供了一种新的治疗方法。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure.

DOI：
10.1124/mol.108.051425
发表时间：
2009-02
期刊：
MOLECULAR PHARMACOLOGY
影响因子：
3.6
作者：
Sankaranarayanan, Ananthakrishnan;Raman, Girija;Busch, Christoph;Schultz, Tim;Zimin, Pavel I.;Hoyer, Joachim;Koehler, Ralf;Wulff, Heike
通讯作者：
Wulff, Heike

Vascular KCa-channels as therapeutic targets in hypertension and restenosis disease.