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: 9903469
• 负责人: Nilkantha Sen
• 金额: $ 34.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-03 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903469
• 关键词: AKT inhibition; Acute; Affect; Antioxidants; Brain-Derived Neurotrophic Factor; CREB Activation Signaling Pathway; Cell Death; Cell Proliferation; Cell membrane; Cell physiology; Cerebral Edema; Cerebrospinal Fluid; Chronic; Clinical; Clinical Trials; Cystathionine beta-Synthase; Cysteine; DLG4 gene; Data; Development; Dose; Edema; Equilibrium; Functional disorder; Genetic Transcription; Goals; Human; Hydrogen Sulfide; Impaired cognition; Impairment; Infarction; Inflammation; Injury; Ipsilateral; Lesion; Maintenance; Measures; Mediating; Memory impairment; Messenger RNA; Monitor; Morbidity - disease rate; Mus; NF-kappa B; Nature; Neurologic; Neurologic Deficit; Neurological outcome; Neurons; Neuroprotective Agents; Outcome; Oxidative Stress; PH Domain; Pathology; Pathway interactions; Patients; Phosphorylation; Prevention; Process; Proliferation Marker; Protein Biosynthesis; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Recovery of Function; Sampling; Stains; Sulfhydryl Compounds; Survivors; Synapses; Synaptic plasticity; Testing; Therapeutic; Therapeutic Agents; Traumatic Brain Injury; Traumatic Brain Injury recovery; Up-Regulation; Vascular Endothelial Growth Factors; Vertebral column; Walking; angiogenesis; base; blood-brain barrier permeabilization; density; disability; drug testing; functional outcomes; hypoxia inducible factor 1; improved; in vivo; injury-related death; innovation; morris water maze; mortality; mutant; neurobehavioral; neurobehavioral test; neurogenesis; neuroprotection; neurovascular injury; novel; novel therapeutic intervention; overexpression; prevent; public health relevance; secondary outcome; small molecule; sulfhydration; therapeutic development

 DESCRIPTION (provided by applicant): 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 and characterized by cell death, edema, neurovascular injury, increase in blood brain barrier permeability, reduction in neurogenesis and neurological impairments. A critical barrier to progress in treating TBI is the absence of effective neuroprotective therapeutics. Most of the neuroprotective 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 angiogenesis/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.

 描述（由申请人提供）：创伤性脑损伤（TBI）是发病率和死亡率的主要原因，每年在美国影响超过170万人。TBI本质上是多因素的，其特征在于细胞死亡、水肿、神经血管损伤、血脑屏障通透性增加、神经发生减少和神经损伤。TBI治疗进展的关键障碍是缺乏有效的神经保护治疗剂。大多数在老鼠身上测试的神经保护药物在人体临床试验中失败了 因为它们针对单一因素，介导TBI中的继发性损伤。我们令人信服的初步数据表明，失活的一个关键的生存蛋白Akt，由气体递质，硫化氢是负责与TBI的结果。TBI诱导的硫化氢增加导致Akt的硫水合作用（Akt-SSH），这导致其催化的 活动和刺激几个次要的结果，导致神经行为障碍后TBI。基于我们的数据，中心假设是除了神经保护之外，抑制Akt-硫水合作用刺激血管生成/神经发生并改善神经学结果以促进TBI后的功能恢复。为了检验我们在特定目标1中的假设，我们将确定TBI诱导的Akt-硫水合作用如何影响Akt活性。在具体目标2中，我们将确定预防Akt-硫水合作用是否改善TBI病理学，并且在具体目标3中，我们将研究Akt-硫水合作用如何影响TBI后的神经发生、脊柱密度和认知障碍。因此，研究抑制Akt-硫酸化的潜力 是一个具有临床意义和转化价值的新建议。该项目的成功完成将展示TBI新治疗模式的可行性，引入减少Akt-硫水合作用水平加速神经保护，神经修复并减少TBI幸存者残疾的概念。