Targeting Sphingosine to Treat Brain Injury

靶向鞘氨醇治疗脑损伤

• 批准号: 9519732
• 负责人: Tatyana I. Gudz
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9519732
• 关键词: Address; American; Attenuated; Behavioral; Biochemical; Bioenergetics; Blast Cell; Brain; Brain Injuries; Cell Death; Ceramidase; Ceramides; Cerebrospinal Fluid; Cerebrum; Complex; Data; Development; Event; FDA approved; Face; Family; Generations; Goals; Head; Helmet; Human; Impaired cognition; Impairment; In Vitro; Inflammatory; Inflammatory Response; Injury; Intervention; Lysosomes; Measurement; Mediating; Metabolism; Methodology; Mitochondria; Modernization; Molecular; Motor; Mus; Neurons; Osteoporosis; Outcome; Oxidative Stress; Pathogenesis; Pharmacology; Pharmacotherapy; Physiological; Play; Process; Publishing; Quality of life; Recovery; Recovery of Function; Research; Role; Shapes; Soldier; Sphingolipids; Sphingomyelins; Sphingosine; System; Testing; Therapeutic Intervention; Training; Trauma; Traumatic Brain Injury; Treatment Efficacy; Up-Regulation; Veterans; acid sphingomyelinase; base; brain tissue; cell injury; clinically relevant; disability; enzyme activity; excitotoxicity; extracellular; improved; in vivo; inhibitor/antagonist; injured; knock-down; mitochondrial dysfunction; mouse model; multidisciplinary; multiple sclerosis treatment; nanoparticle delivery; novel; novel therapeutic intervention; programs; public health relevance; tandem mass spectrometry; therapeutic target

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) accounts for a significant number of casualties sustained by our soldiers, leaving many of them with substantial motor disabilities and cognitive impairments. There are no pharmacological interventions for brain trauma, mainly because the molecular and cellular mechanisms comprising brain injury remain unclear. Our current understanding of the pathogenesis of TBI suggests a dynamic interplay at the cellular level between excitotoxicity, oxidative stress, inflammatory events, and mitochondrial dysfunction, which occurs over days, weeks and months. Compelling evidence suggests that mitochondrial damage plays a crucial and central role in determining the outcome, since mitochondria are involved in regulating oxidative stress, inflammatory response, and cell death. The proposed studies are aimed at determining the mechanisms of mitochondrial damage focusing on a novel role of a toxic sphingolipid, sphingosine, as a cause of mitochondrial dysfunction following brain trauma. Our preliminary and published studies suggest that TBI provokes continued up-regulation of mitochondrial sphingosine, which could impact a number of mitochondrial functions, leading to persisting mitochondrial dysfunction after the primary insult. The long-term goal of the proposed studies is to develop a neuroprotective strategy based on attenuating sphingosine-dependent brain impairment after TBI. The central hypothesis of our proposal is that TBI-induced accumulation of sphingosine in mitochondria results in mitochondrial dysfunction, leading to neural cell injury and secondary brain damage. We plan to test our hypothesis by pursuing 2 specific aims: 1) Determine the mechanisms of the neutral ceramidase-mediated mitochondrial sphingosine generation and brain injury; 2) Determine the mechanisms of the acid sphingomyelinase-dependent mitochondrial sphingosine accumulation and brain injury. Fingolimod, an FDA- approved drug for treatment of multiple sclerosis, and Reclast, an FDA-approved drug for treatment of osteoporosis, will be utilized to inhibit sphingosine generation, reducing brain damage and preserving the brain function after TBI. We will use a multi-disciplinary and integrative approach, combining in vitro and in vivo studies in a mouse model of TBI with modern pharmacological, biochemical and bioenergetics methodologies. A powerful, state-of-the-art methodology, tandem mass spectrometry, will be utilized for assessment of sphingolipid- producing enzyme activities and precise measurement of the sphingolipid profile. The proposed studies will help us decipher novel sphingosine-mediated mechanisms of TBI and will lead to the development of effective therapeutic strategies to protect the brain from secondary injury, improving brain function recovery for Veterans with TBI.

 描述(由申请人提供)： 创伤性脑损伤(TBI)是造成我军士兵大量伤亡的重要原因，其中许多人存在严重的运动障碍和认知障碍。目前还没有针对脑损伤的药物干预措施，主要是因为构成脑损伤的分子和细胞机制尚不清楚。我们目前对TBI发病机制的理解表明，兴奋性毒性、氧化应激、炎症事件和线粒体功能障碍在细胞水平上存在动态相互作用，这些功能可以发生在数天、数周和数月的时间内。令人信服的证据表明，线粒体损伤在决定预后中起着关键和核心的作用，因为线粒体参与调节氧化应激、炎症反应和细胞死亡。拟议的研究旨在确定线粒体损伤的机制，重点是有毒鞘糖脂作为脑创伤后线粒体功能障碍的原因所起的新作用。我们的初步研究和已发表的研究表明，脑外伤引起线粒体鞘氨醇的持续上调，这可能会影响线粒体的一些功能，导致原发损伤后持续的线粒体功能障碍。这项拟议研究的长期目标是开发一种基于减轻脑外伤后鞘氨醇依赖性脑损伤的神经保护策略。我们的建议的中心假设是，脑外伤引起的神经鞘氨醇在线粒体中的积聚导致线粒体功能障碍，导致神经细胞损伤和继发性脑损伤。我们计划通过两个特定的目标来验证我们的假说：1)确定中性神经酰胺酶介导的线粒体鞘氨醇生成和脑损伤的机制；2)确定酸性鞘磷脂酶依赖的线粒体鞘氨醇积累和脑损伤的机制。FDA批准的治疗多发性硬化症的药物Fingolimod和FDA批准的治疗骨质疏松症的药物Reclast将被用于抑制鞘氨醇的产生，减少脑损伤，并保护脑损伤后的脑功能。我们将使用多学科和综合的方法，结合在体外和体内对脑外伤小鼠模型的研究，以及现代药理学、生化和生物能量学方法。一种强大的、最先进的方法，串联质谱仪，将被用来评估鞘脂脂产生酶的活性和精确测量鞘脂脂的分布。这些研究将帮助我们破译新的鞘氨醇介导的脑损伤机制，并将导致开发有效的治疗策略来保护大脑免受继发性损伤，促进退伍军人脑损伤后的脑功能恢复。