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Therapeutics of mTOR Signaling in Succinic Semialdehyde Dehydrogenase Deficiency

mTOR 信号转导治疗琥珀酸半醛脱氢酶缺乏症

基本信息

批准号：
8848901
负责人：
K Michael GIBSON
金额：
$ 22.26万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848901
关键词：
4-Aminobutyrate aminotransferase 4-hydroxybutyric acid Abbreviations Amino Acids Analysis of Variance Animals Antiepileptic Agents Autophagocytosis Beak Biochemical Biological Markers Brain Cells Clinical Clinical Trials Complex Coupled Coupling Data Disease Disease model Evaluation Focal Seizure Health Hepatocyte Hereditary Disease Homologous Gene Human Human Biology In Vitro Infantile spasms Intervention Investigation Laboratories Lead Liver Longevity Mediating Metabolism Mitochondria Modeling Mus Neuraxis Neuromodulator Neurons Neurotransmitters Organelles Outcome Outcome Measure Oxidative Stress Pathology Pathway interactions Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenocopy Phenotype Physiological Pilot Projects Process Research Design Ribosomal Protein S6 Kinase Role Route SGS-742 Seizures Signal Transduction Sirolimus Succinate-semialdehyde dehydrogenase Succinate-semialdehyde dehydrogenase deficiency System Taurine Therapeutic Vigabatrin Work Yeasts aldehyde dehydrogenases aminobutyrate animal data base clinically relevant combinatorial gamma-Aminobutyric Acid human FRAP1 protein improved in vivo in vivo Model inhibitor/antagonist innovation insight knowledge base mTOR Inhibitor mTOR inhibition nervous system disorder novel novel therapeutics oxidative damage peroxisome pre-clinical receptor success

项目摘要

DESCRIPTION (provided by applicant): Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1) deficiency remains the most prevalent disorder of GABA (4-aminobutyrate) metabolism, one that is unique in the accretion of two neuromodulators, GABA and GHB (gamma-hydroxybutyric acid). Some 30 years after its discovery, effective pharmacotherapy remains elusive. We recently unmasked in yeast an unexpected role for GABA as an inhibitor of selective autophagy pathways, pexophagy and mitophagy, a process mediated via Sch9 (homolog of mammalian ribosomal S6 kinase 1, S6K1) activation and associated with oxidative damage. Pilot studies have demonstrated that intervention with the mTOR inhibitor, rapamycin, which down-regulates Sch9, can significantly mitigate GABA-related pathology in the murine model, including reducing increased mitochondrial number, improving oxidative stress parameters, and mitigating aberrant cell signaling. Our primary hypothesis posits that therapeutics inhibiting mTOR signaling and/or inducing autophagy will provide an innovative therapeutic approach to heritable disorders featuring GABA elevation, while informing pharmacotherapies that target increased GABA increase in central nervous system (CNS). Aim 1 will examine the physiological, biochemical and cellular effects of mTOR inhibition (rapamycin, torin1, temsirolimus) in aldh5a1-/- mice. Aim 2 will examine the capacity of selected drugs to override disruptions of pexophagy and mitophagy in primary cultures of aldh5a1-/- cells. Our study design will be a 2x2 factorial mixed model for both aims, employing ANOVA with post hoc analyses for statistical analyses. Our rationale for combined cellular and animal studies centers on our prediction that in vitro studies will serve to elucidate GABA-related pathomechanisms, while in vivo studies will outline a more rapid route to clinical intervention. This project will beak new scientific ground on the role of GABA in human biology, accrue preclinical animal data that will pave the way for novel therapeutics in disorders with elevated CNS GABA, and provide new insights on the use of selected antiepileptics whose pharmacological objective is to increase GABA. We are evaluating rational therapies based upon our pilot studies, but these therapies cannot be piloted in humans without additional preclinical data. Our laboratory has already spring-boarded preclinical animal data using taurine and SGS-742 into human clinical trials in SSADH deficiency, underscoring the potential for success in the current project.

描述（由申请人提供）：琥珀酸半醛脱氢酶（SSADH;醛脱氢酶5a 1）缺乏症仍然是GABA（4-氨基丁酸）代谢的最常见疾病，在GABA和GHB（γ-羟基丁酸）两种神经调节剂的增加中是独特的。在其发现后的30年里，有效的药物治疗仍然难以捉摸。我们最近在酵母中发现了GABA作为选择性自噬途径，pexophagy和mitophagy的抑制剂的意想不到的作用，这是一个通过Sch 9（哺乳动物核糖体S6激酶1，S6 K1的同源物）激活介导的过程，并与氧化损伤相关。初步研究表明，用下调Sch 9的mTOR抑制剂雷帕霉素进行干预可以显著减轻小鼠模型中GABA相关的病理学，包括减少线粒体数量增加，改善氧化应激参数，并减轻异常细胞信号传导。我们的主要假设假定，抑制mTOR信号传导和/或诱导自噬的疗法将为以GABA升高为特征的遗传性疾病提供创新的治疗方法，同时为靶向中枢神经系统（CNS）中增加的GABA增加的药物疗法提供信息。目的1将检查aldh 5a 1-/-小鼠中mTOR抑制（雷帕霉素、torin 1、替西罗莫司）的生理、生化和细胞效应。目的2将检测所选药物克服aldh 5a 1-/-细胞原代培养物中细胞自噬和线粒体自噬破坏的能力。我们的研究设计将是两个目标的2x2析因混合模型，采用ANOVA和事后分析进行统计分析。我们的理论基础相结合的细胞和动物研究中心，我们的预测，在体外研究将有助于阐明GABA相关的病理机制，而在体内研究将勾勒出一个更快速的路线，以临床干预。该项目将为GABA在人类生物学中的作用奠定新的科学基础，积累临床前动物数据，为CNS GABA升高的疾病的新型治疗方法铺平道路，并为使用选定的抗癫痫药提供新的见解，其药理学目的是增加GABA。我们正在根据我们的试点研究评估合理的治疗方法，但如果没有额外的临床前数据，这些治疗方法无法在人体中试点。我们的实验室已经将牛磺酸和SGS-742的临床前动物数据用于SSADH缺乏症的人体临床试验，强调了当前项目成功的潜力。