Development of therapeutic strategy against TBI based on hydrogen sulfide

基于硫化氢的 TBI 治疗策略的开发

• 批准号: 9175254
• 负责人: Nilkantha Sen
• 金额: $ 33.25万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9175254
• 关键词: Affect; Aftercare; Astrocytes; Attenuated; Boxing; Brain-Derived Neurotrophic Factor; CREB1 gene; Cell Death; Cell membrane; Cell physiology; Cerebral Edema; Cerebrospinal Fluid; Cessation of life; Clinical; Clinical Trials; Complex; Confocal Microscopy; Cystathionine beta-Synthase; Cysteine; Data; Development; Edema; Event; Functional disorder; Goals; Human; Hydrogen Sulfide; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Measures; Mediating; Memory impairment; Messenger RNA; Modeling; Monitor; Morbidity - disease rate; Mus; Nature; Neurologic; Neurological outcome; Neurons; Outcome; Pathology; Pathway interactions; Patients; Phosphorylation; Prevention; Process; Protective Agents; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Recovery of Function; Sampling; Sulfhydryl Compounds; Survivors; Testing; Therapeutic; Therapeutic Agents; Transcriptional Activation; Traumatic Brain Injury; Traumatic Brain Injury recovery; Vertebral column; Walking; Western Blotting; base; cell type; cytokine; density; disability; drug testing; functional outcomes; improved; in vivo; inhibitor/antagonist; innovation; morris water maze; mortality; mutant; neurobehavioral; neurobehavioral test; neurogenesis; neuroprotection; novel; novel therapeutic intervention; outcome prediction; overexpression; prevent; secondary outcome; small molecule; sulfhydration; therapeutic development

Traumatic Brain Injury (TBI) is a major cause of morbidity and mortality and it affects more than 1.7 million people in the USA per year. TBI is multifactorial in nature however cerebral edema with robust inflammatory responses remains the most significant predictor of outcome of TBI. A critical barrier to progress in treating TBI is the absence of effective neuro-protective therapeutics. Most of the neuro-protective drugs tested in mice have failed in human clinical trials because they target a single factor, which mediates secondary injury in TBI. Our compelling preliminary data suggests that inactivation of a key survival protein Akt, by a gasotransmitter, hydrogen sulfide is responsible for outcomes associated with TBI. TBI-induced increase in hydrogen sulfide causes sulfhydration of Akt (Akt-SSH) which leads to inactivation of its catalytic activity and stimulates several secondary outcomes that leads to neurobehavioral impairment following TBI. Based on our data the central hypothesis is that in addition to neuroprotection, inhibition of Akt-sulfhydration stimulates neurogenesis and improves neurological outcomes to promote functional recovery after TBI. To test our hypothesis in Specific Aim 1 we will determine how TBI induced Akt-sulfhydration affects Akt activity. In specific Aim 2 we will determine whether prevention of Akt-sulfhydration improves TBI-pathology, and in specific aim 3 we will study how Akt-sulfhydration impacts neurogenesis, spine density and cognitive impairment following TBI. Therefore, investigating the potential of inhibition of Akt-sulfhydration in TBI is a novel proposal with clinical implications and translational value. Successful accomplishment of this project will show the feasibility of a new treatment paradigm for TBI, introducing the concept that reduction in the level of Akt-sulfhydration accelerates neuroprotection, neurorepair and reduces disabilities in TBI survivors.

创伤性脑损伤 (TBI) 是发病率和死亡率的主要原因，影响超过 170 万人 每年在美国的人数。 TBI 本质上是多因素的，但脑水肿伴有强烈的炎症 反应仍然是 TBI 结果最重要的预测因素。 TBI 治疗取得进展的一个关键障碍 是缺乏有效的神经保护疗法。大多数神经保护药物都在小鼠身上进行了测试 在人体临床试验中失败了，因为它们针对的是单一因素，该因素介导了 TBI 的继发性损伤。 我们令人信服的初步数据表明，气体递质使关键生存蛋白 Akt 失活， 硫化氢是导致 TBI 相关结果的原因。 TBI 引起的硫化氢增加 导致 Akt (Akt-SSH) 硫化，导致其催化活性失活并刺激多种 TBI 后导致神经行为损伤的次要结果。根据我们的数据，中央 假设除了神经保护作用外，抑制 Akt 硫化作用还能刺激神经发生， 改善神经系统结果，促进 TBI 后的功能恢复。为了检验我们的假设 目标 1 我们将确定 TBI 诱导的 Akt 硫化作用如何影响 Akt 活性。在具体目标 2 中，我们将 确定预防 Akt 硫化作用是否可以改善 TBI 病理学，在具体目标 3 中，我们将研究 Akt-硫化物如何影响 TBI 后的神经发生、脊柱密度和认知障碍。所以， 研究 TBI 中 Akt 硫酸化抑制的潜力是一项具有临床意义的新提议 和翻译价值。该项目的成功完成将证明新治疗方法的可行性 TBI 的范例，引入了 Akt 硫化水平降低加速的概念 神经保护、神经修复并减少 TBI 幸存者的残疾。