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：
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
项目类别：
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

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5A1）缺乏症仍然是GABA（4-氨基丁酸）代谢的最普遍的疾病，一种在两种神经抑制剂中具有独特性，它是独特的。发现后约30年，有效的药物治疗仍然难以捉摸。我们最近在酵母中揭露了GABA作为选择性自噬途径，Pexophagy and Mitophagy的抑制剂的意外作用，这是通过SCH9（哺乳动物核糖体S6激酶1，S6K1）激活介导的过程，并与氧化损伤相关。试点研究表明，下调SCH9的MTOR抑制剂Rapamycin的干预可以显着减轻鼠模型中与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。我们的主要假设认为，抑制MTOR信号传导和/或诱导自噬的治疗学将为具有GABA升高的可遗传性疾病提供创新的治疗方法，同时告知靶向GABA增加中枢神经系统（CNS）的GABA增加的药物治疗。 AIM 1将检查MTOR抑制作用（雷帕霉素，torin1，temsirolimus）的生理，生化和细胞作用。 AIM 2将检查选定药物在Aldh5A1-/ - 细胞原代培养物中覆盖质量破坏和线粒体的破坏的能力。我们的研究设计将是两个目标的2x2阶乘混合模型，并采用ANOVA进行了HOC后分析进行统计分析。我们的细胞和动物研究的基本原理是基于我们的预测，即体外研究将有助于阐明与GABA相关的病理机制，而体内研究将概述更快的临床干预途径。该项目将在GABA在人类生物学中的作用，促进临床前动物数据的新科学基础，这将为CNS GABA升高的疾病中的新型治疗铺平道路，并就使用药理学目标增加GABA的选定抗血清动物的使用提供了新的见解。我们正在根据试点研究评估有理疗法，但是如果没有其他临床前数据，这些疗法就无法在人类中进行试验。我们的实验室已经使用牛磺酸和SGS-742弹出临床前动物数据进入了SSADH缺乏症的人类临床试验，从而强调了当前项目成功的潜力。