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）：琥珀半醛脱氢酶（SSADH；乙醛脱氢酶 5a1）缺乏症仍然是 GABA（4-氨基丁酸）代谢最普遍的疾病，这种疾病在两种神经调节剂 GABA 和 GHB（γ-羟基丁酸）的积累中是独一无二的。酸）。其发现约 30 年后，有效的药物疗法仍然难以捉摸。我们最近在酵母中揭示了 GABA 作为选择性自噬途径（pexophagy 和 mitophagy）抑制剂的意想不到的作用，这是一种通过 Sch9（哺乳动物核糖体 S6 激酶 1，S6K1 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，使用下调 Sch9 的 mTOR 抑制剂雷帕霉素进行干预，可以显着减轻小鼠模型中 GABA 相关的病理，包括减少线粒体数量增加、改善氧化应激参数和减轻异常细胞信号传导。我们的主要假设认为，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，同时为针对中枢神经系统 (CNS) 中 GABA 增加的药物疗法提供信息。目标 1 将检查 mTOR 抑制（雷帕霉素、torin1、替西罗莫司）对 aldh5a1-/- 小鼠的生理、生化和细胞影响。目标 2 将检查所选药物在 aldh5a1-/- 细胞原代培养物中克服 pexophagy 和 mitophagy 破坏的能力。我们的研究设计将是针对这两个目标的 2x2 因子混合模型，采用方差分析和事后分析进行统计分析。我们结合细胞和动物研究的基本原理集中在我们的预测上，即体外研究将有助于阐明 GABA 相关的病理机制，而体内研究将概述更快速的临床干预途径。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，为中枢神经系统 GABA 升高疾病的新疗法铺平道路，并提供有关使用选定抗癫痫药的新见解，其药理学目标是增加GABA。我们正在根据我们的试点研究评估合理的疗法，但如果没有额外的临床前数据，这些疗法无法在人类身上进行试点。我们的实验室已经使用牛磺酸和 SGS-742 将临床前动物数据转移到 SSADH 缺乏症的人体临床试验中，强调了当前项目成功的潜力。