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

• 批准号: 8769623
• 负责人: K Michael GIBSON
• 金额: $ 20.98万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769623
• 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; 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; 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; public health relevance; receptor; ribosomal protein S6 kinase 1; success

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；乙醛脱氢酶5a1)缺乏仍然是GABA(4-氨基丁酸)代谢最普遍的障碍，这是在两种神经调节剂GABA和GHB(伽马-羟基丁酸)的增加中独一无二的。在它被发现大约30年后，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、附着性吞噬和有丝分裂吞噬的抑制因子的意想不到的作用，这一过程通过Sch9(哺乳动物核糖体S6激酶1的同源物，S6K1)激活而介导，并与氧化损伤有关。初步研究表明，mTOR抑制剂雷帕霉素下调Sch9的表达，可以显著减轻小鼠模型中与GABA相关的病理，包括减少增加的线粒体数量，改善氧化应激参数，以及减轻异常细胞信号。我们的主要假设是，抑制mTOR信号转导和/或诱导自噬的治疗方法将为以GABA升高为特征的遗传性疾病提供一种创新的治疗方法，同时告知药物治疗的靶点是中枢神经系统(CNS)中GABA增加。目的1研究mTOR抑制(雷帕霉素、托林1、替西罗莫斯)对aldh5a1-/-小鼠的生理、生化和细胞效应。目的2将检查选定的药物在原代培养的aldh5a1-/-细胞中克服吞噬作用和有丝分裂作用中断的能力。我们的研究设计将是两个目标的2x2因子混合模型，使用ANOVA和事后分析进行统计分析。我们的细胞和动物联合研究的理论基础是我们的预测，即体外研究将有助于阐明GABA相关的病理机制，而体内研究将勾勒出一条更快速地进行临床干预的途径。该项目将为GABA在人类生物学中的作用开辟新的科学基础，积累临床前动物数据，为治疗中枢神经系统GABA升高的疾病提供新的治疗方法，并为选择药理目的是增加GABA的抗癫痫药物的使用提供新的见解。我们正在根据我们的试点研究评估合理的疗法，但这些疗法在没有额外的临床前数据的情况下无法在人类身上进行试点。我们的实验室已经将使用牛磺酸和SGS-742的临床前动物数据应用到治疗SSADH缺乏症的人类临床试验中，强调了当前项目成功的潜力。