ConProject-001

基本信息

批准号：
10316591
负责人：
Ilya B Bezprozvanny
金额：
$ 72.31万
依托单位：
CHAPMAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316591
关键词：
Affect Ataxia Behavioral Binding Biological Process Calcium Calcium Signaling Cells Cerebellar Ataxia Cessation of life Clinical Clinical Research Collaborations Complex Computational Biology Crystallization Development Disease Dominant Genetic Conditions Drug Targeting Electrophysiology (science)Equilibrium Exposure to Fluorescence Functional disorder Future Genetic Goals Health ITPR1 gene Industrialization Inositol Knowledge Laboratories Letters Metabolic Methods Movement Mus Muscle Nerve Degeneration Neurodegenerative Disorders Neurons Online Mendelian Inheritance In Man Pathogenesis Pathology Patients Pattern Phase Phenotype Play Population Potassium Pre-Clinical Model Proteins Purkinje Cells Research Riluzole Role SCA2 protein Signal Transduction Slice Specificity Spinocerebellar Ataxias Structure Symptoms Testing Therapeutic Therapeutic Agents Transgenic Mice Type 2 Spinocerebellar Ataxia base biophysical techniques clinical development effective therapy high throughput screening interest mouse model mutant nervous system disorder novel novel therapeutics polyglutamine positive allosteric modulator pre-clinical preclinical development prototype receptor skills structural biology therapeutically effective tool translational neuroscience virtual

Affect Ataxia Behavioral Binding Biological Process Calcium Calcium Signaling Cells Cerebellar Ataxia Cessation of life Clinical Clinical Research Collaborations Complex Computational Biology Crystallization Development Disease Dominant Genetic Conditions Drug Targeting Electrophysiology (science)Equilibrium Exposure to Fluorescence Functional disorder Future Genetic Goals Health ITPR1 gene Industrialization Inositol Knowledge Laboratories Letters Metabolic Methods Movement Mus Muscle Nerve Degeneration Neurodegenerative Disorders Neurons Online Mendelian Inheritance In Man Pathogenesis Pathology Patients Pattern Phase Phenotype Play Population Potassium Pre-Clinical Model Proteins Purkinje Cells Research Riluzole Role SCA2 protein Signal Transduction Slice Specificity Spinocerebellar Ataxias Structure Symptoms Testing Therapeutic Therapeutic Agents Transgenic Mice Type 2 Spinocerebellar Ataxia base biophysical techniques clinical development effective therapy high throughput screening interest mouse model mutant nervous system disorder novel novel therapeutics polyglutamine positive allosteric modulator pre-clinical preclinical development prototype receptor skills structural biology therapeutically effective tool translational neuroscience virtual

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项目摘要

The broad, long-term objective of the project is to develop novel therapeutic agents for spinocerebellar ataxias (SCAs). There is no effective treatment or cure for SCAs, in large part due to insufficient understanding of the disease pathogenesis. In this project, we will focus on spinocerebellar ataxia type 2 (SCA2). SCA2 is an autosomal dominant genetic neurodegenerative disorder caused by polyQ expansion in ataxin-2 (Atxn2) protein. Cerebellar Purkinje cells (PCs) are the main locus of pathology in SCA2 patients. Previously, our laboratory discovered abnormal neuronal calcium signaling in PCs, which play an important role in the pathogenesis of SCAs. Previous studies also suggest that neuronal activity of PCs is abnormal in ataxic mouse models. We demonstrated that positive allosteric modulators (PAMs) of small conductance calcium-activated potassium (SK) channels can normalize the abnormal firing pattern of PCs in SCA2 mice and alleviate behavioral and neuropathological phenotypes. These results suggest that SK PAMs can be potentially useful as therapeutic agents for the treatment of SCA2 and possibly for other ataxias. This project brings together the complementary skills and expertise of two laboratories for the discovery of such agents. To achieve this goal, we will focus on the following specific aims: R21 Phase Aim 1. To identify novel subtype-selective SK PAM candidates. We will determine the crystal structure of SK2 channels in complex with the prototype subtype-selective PAMs. We will obtain structural information that will be used to perform v irtual high throughput screening for subtype-selective SK PAMs. R21 Phase Aim 2. To validate functional activity of novel SK PAMs. We will use fluorescence-based high throughput assay and electrophysiological methods to test SK PAM candidates. R33 Phase Aim 3. To investigate the specificity of novel SK PAMs for SK channels. We will evaluate the specificity of the SK PAM candidates for SK channels over other K+, Na+ and Ca2+ channels using electrophysiological recordings. R33 Phase Aim 4. To investigate the effects of novel SK PAMs on the activity of cerebellar PCs in SCA2 mice. We will perform ex. vivo. cerebellar slice electrophysiological recordings of PC activity in these studies. The resulting subtype-selective SK PAMs will provide critical leads for future preclinical and clinical development, fulfilling the critical and unmet needs in ataxia patients. These molecules will also offer novel and unique research tools for understanding the biological function of SK channels in health and disease. Thus, the proposed project will have significant impact in basic and translational neuroscience.

该项目的广泛长期目标是开发新型的脊髓脑性苯甲酸治疗剂（SCA）。 SCA没有有效的治疗方法，在很大程度上是由于对疾病发病机理。在这个项目中，我们将重点介绍2型2型（SCA2）。 Sca2是一个 polyq膨胀引起的共染色体遗传神经退行性疾病是由polyq扩展引起的（ATXN2）蛋白质。小脑普林吉细胞（PC）是SCA2患者病理学的主要基因座。以前，我们的实验室在PC中发现了异常的神经元信号传导，在PC中起着重要作用 SCAS的发病机理。先前的研究还表明，PC的神经元活性在共透小鼠中是异常的型号。我们证明了小电导钙激活的阳性变构调节剂（PAM）钾（SK）通道可以使SCA2小鼠PC的异常射击模式正常化并减轻行为和神经病理表型。这些结果表明SK PAM可能有用作为治疗SCA2及其他共济失调治疗的治疗剂。这个项目汇集了两个实验室发现此类代理商的补充技能和专业知识。为了实现这一目标，我们将专注于以下特定目标： R21阶段目标1。确定新型亚型选择性SK PAM候选物。我们将确定晶体 SK2通道的结构与原型亚型选择性PAM的复合物。我们将获得结构用于对亚型选择性SK PAM进行V型高吞吐量筛选的信息。 R21阶段目标2。验证新型SK PAM的功能活性。我们将使用基于荧光的高吞吐量测定和电生理方法测试SK PAM候选物。 R33阶段目标3。研究新型SK PAM对SK通道的特异性。我们将评估使用其他K+，Na+和Ca2+通道的SK PAM候选者的特异性使用电生理记录。 R33阶段目标4。研究新型SK PAM对小脑PC在SCA2中活性的影响老鼠。我们将执行EX。体内。这些研究中PC活性的小脑切片电生理记录。由此产生的亚型选择性SK PAM将为未来的临床前和临床提供关键的潜在客户开发，满足共济失调患者的关键和未满足的需求。这些分子也将提供小说以及了解SK渠道在健康和疾病中的生物学功能的独特研究工具。因此，拟议的项目将对基本和翻译神经科学产生重大影响。