权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Targeting TRPC3 Channels for Epileptic Seizures

针对癫痫发作的 TRPC3 通道

基本信息

批准号：
10531252
负责人：
Jianxiong Jiang
金额：
$ 38万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531252
关键词：
Ablation Acute Adverse effects Affect Amides Animals Anticonvulsants Antiepileptogenic Behavioral Brain Brain Diseases Brain-Derived Neurotrophic Factor Carboxylic Acids Cations Chemical Structure Chronic Cognitive Cognitive deficits Darkness Development Diagnosis Diazepam Disease Progression Dose Drug Exposure Drug Kinetics Electroencephalography Epilepsy Epileptogenesis Esters Event FDA approved Family Frequencies Future Generations Genetic Glial Fibrillary Acidic Protein Gliosis Goals Half-Life Hippocampus Human Hydrolysis Impairment Lead Legal patent Light Mediating Metabolic Modeling Molecular Conformation Mus Neocortex Outcome Pathologic Patients Penetration Persons Pharmaceutical Preparations Phase Phosphotransferases Pilocarpine Plasma Population Populations at Risk Pre-Clinical Model Property Pyrazoles Quality of life Recurrence Research Role Safety Seizures Series Severities Signal Transduction Status Epilepticus Stroke Structure TRP channel Tail Testing Time Toxic effect Traumatic Brain Injury Treatment Protocols Tropomyosin acquired epilepsy analog anxiety-like behavior cognitive testing comorbidity design experience high risk hippocampal pyramidal neuron improved in vivo inhibitor lead optimization member meter mouse model neocortical nervous system disorder neuron loss neuropathology novel novel therapeutics object recognition pharmacokinetics and pharmacodynamics preclinical study prevent receptor scaffold scale up side effect therapeutic target therapy outcome

项目摘要

PROJECT SUMMARY As one of the most common brain disorders, epilepsy afflicts about 1% of the world population. Despite recent marked advances in seizure management, there are still more than 30% of patients poorly responding to current anti-seizure drugs (ASDs), which can cause wide-ranging and often unbearable side effects. It is another very unfortunate fact that current ASDs merely provide symptomatic relief, and no FDA-approved medication has been demonstrated to prevent the development of epilepsy in people at risks or modify the disease progression in those diagnosed with epilepsy. Developing safer, more effective anti-seizure and/or anti-epileptogenic therapies is in urgent unmet demand. Transient receptor potential canonical 3 (TRPC3) is a member of TRP family channels that control Ca2+ influxes. TRPC3 is found abundant in neocortex and hippocampus, where it colocalizes with brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase receptor B (TrkB), regulating BDNF/TrkB signaling- mediated dendritic remodeling in pyramidal neurons. Mounting evidence from recent studies suggest that the excessive BDNF/TrkB activity contributes to spontaneous recurrent seizures (SRSs) after status epilepticus (SE), indicative of a role of TRPC3 in epileptic seizures. Genetic ablation of TRPC3 reduces pilocarpine- induced seizures in mice, suggesting that TRPC3 inhibition might represent a novel anti-seizure and/or anti- epileptogenic strategy. Among TRPC3 inhibitors that emerged during the past decade, Pyr3 is most selective and thus widely used to study TRPC3-mediated Ca2+ entry in various pathological conditions. However, the chemical structure of Pyr3 poses a number of major liabilities including low metabolic stability caused by rapid hydrolysis of its ester moiety, leading to inactive carboxylic acid metabolite. Our overarching goal is to – using rationale design – develop a lead TRPC3 inhibitor with high metabolic stability, low toxicity, as well as favorable pharmacodynamic and pharmacokinetic properties (R61 phase). We will then determine its ability to suppress acute seizures, prevent SRSs (epileptogenesis), and/or improve cognitive outcomes (R33 phase). Upon successful completion, we will have established a proof-of-concept for TRPC3 inhibition as a novel anti- seizure and/or anti-epileptogenic strategy in a classical mouse model of epilepsy and a patented lead molecule for further development. Anticipated results will justify future studies on safety, efficacy, and more extensive lead-optimization if needed to develop a new therapy to prevent and/or suppress acquired epilepsy in patients suffering from putative seizure-precipitating events, such as de novo SE, traumatic brain injuries, etc.

项目摘要作为最常见的脑部疾病之一，癫痫困扰着约1%的世界人口。尽管最近尽管癫痫发作管理取得了显著进展，但仍有超过30%的患者对目前的抗癫痫药物（ASD），这可能会导致广泛的，往往难以忍受的副作用。是另一个非常不幸的事实是，目前的ASD仅仅提供症状缓解，没有FDA批准的药物治疗已被证明可以预防处于风险中的人癫痫的发展或改变疾病进展在那些被诊断为癫痫。开发更安全、更有效的防癫痫和/或抗癫痫治疗的需求迫切得不到满足。瞬时受体电位经典3（TRPC 3）是TRP家族的一个成员，控制Ca2 + 流入TRPC 3在新皮层和海马体中被发现是丰富的，在那里它与脑源性的神经营养因子（BDNF）和原肌球蛋白相关激酶受体B（Trk B），调节BDNF/Trk B信号传导- 介导的锥体神经元树突重塑。最近的研究表明，过量的BDNF/TrkB活性有助于癫痫持续状态后自发性复发性癫痫发作（SRS） (SE)，表明TRPC 3在癫痫发作中的作用。TRPC 3基因切除减少毛果芸香碱- 诱导小鼠癫痫发作，表明TRPC 3抑制可能代表一种新的抗癫痫和/或抗癫痫药物。致痫策略在过去十年中出现的TRPC 3抑制剂中，Pyr3是最具选择性的，因此被广泛用于研究TRPC 3介导的各种病理条件下的Ca2+内流。Pyr3的化学结构造成了许多主要的不利因素，包括由其酯的快速水解引起的低代谢稳定性部分，导致无活性的羧酸代谢物。我们的首要目标是-使用基本原理设计- 开发一种具有高代谢稳定性、低毒性以及有利的TRPC 3先导抑制剂，药效学和药代动力学特性（R61阶段）。然后我们将确定它抑制急性癫痫发作，预防SRS（癫痫发生）和/或改善认知结果（R33期）。成功完成后，我们将建立TRPC 3抑制作为一种新的抗肿瘤药物的概念验证。癫痫的经典小鼠模型中的癫痫发作和/或抗癫痫策略以及专利的先导分子进一步发展。预期的结果将证明未来的安全性，有效性和更广泛的研究是合理的。如果需要开发新疗法以预防和/或抑制患者的获得性癫痫，则进行电极导线优化患有假定的癫痫突发事件，如新发SE、创伤性脑损伤等。