Investigating and treating metabolic deficits in the neurovascular unit following mild traumatic brain injury

研究和治疗轻度创伤性脑损伤后神经血管单元的代谢缺陷

• 批准号: 10557546
• 负责人: William Brad Hubbard
• 金额: $ 27.54万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557546
• 关键词: Acute; Alzheimer' s Disease; Bioenergetics; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Carbon; Centers of Research Excellence; Cerebrovascular Circulation; Chronic; Citric Acid Cycle; Classification; Data; Disease; Dose; Drug Targeting; Endothelial Cells; Enhancers; Euthanasia; Female; Fostering; Foundations; Freezing; Functional disorder; Future; Genus Hippocampus; Glutamates; Glycolysis; Hippocampus; Impaired cognition; Impairment; Injury; Label; Long-Term Effects; Magnetic Resonance Imaging; Magnetism; Mass Fragmentography; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Neuroglia; Neurons; Nicotinamide Mononucleotide; Outcome; Oxidative Stress; Pathologic; Pathology; Patients; Pericytes; Procedures; Proteins; Public Health; Pyruvate; Rattus; Reporting; Resources; Sprague-Dawley Rats; Synapses; Techniques; Therapeutic; Therapeutic Effect; Tight Junctions; Traumatic Brain Injury; acute symptom; axonal degeneration; brain tissue; cell type; cellular targeting; cerebral capillary; cohort; dementia risk; design; functional outcomes; innovation; insight; male; metabolomics; mild traumatic brain injury; mitochondrial dysfunction; neural; neurobehavioral; neuron loss; neurovascular unit; novel; oxidative damage; primary outcome; protective efficacy; repaired; response; restoration; small molecule; therapeutic development; therapeutic target

Traumatic brain injuries (TBIs) are a major societal and public health concern with over 1.7 million TBIs, ~80% of which mild, are reported each year in the US. TBI is also a major risk factor for dementias and Alzheimer’s Disease. Mild TBI is characterized by dysfunction of the neurovascular unit (NVU), initiated by breakdown of the blood-brain barrier and followed by synaptic dyshomeostasis. Mitochondrial dysfunction is apparent in the NVU after mild TBI, accompanied by metabolic imbalance and oxidative damage. This project will examine the metabolic deficits of distinct components of the NVU, including neuronal synapse and brain capillaries, by using steady state metabolomics as well as intra-mitochondrial metabolic tracing following mild TBI. These results will be generated in conjunction with profiling of mitochondrial bioenergetics of the NVU components. These studies will directly use the resources provided by the CNS-Met Metabolomics Core. P7C3- A20, which elevates NAD+ and demonstrates efficacy in TBI models, will be administered alongside nicotinamide mononucleotide, which is a NAD+ precursor, to examine therapeutic effect at restoring alterations in metabolism and functional outcomes. The completion of these studies will generate an enhanced understanding of mitochondrial dysfunction and metabolite flux in distinct components of the NVU following mild TBI and provide supportive data on a pathology-modifying drugs targeting NAD+ to treat this disease.

创伤性脑损伤（TBI）是一个主要的社会和公共卫生问题，有超过170万TBI， 其中约80%为轻度，每年在美国报告。TBI也是痴呆症的主要危险因素， 老年痴呆症轻度TBI的特征在于神经血管单位（NVU）的功能障碍，由以下引起： 血脑屏障的破坏和随后的突触稳态障碍。线粒体功能紊乱是 在轻度TBI后的NVU中明显，伴有代谢失衡和氧化损伤。这个项目 将检查NVU不同组成部分的代谢缺陷，包括神经元突触和大脑 毛细血管，通过使用稳态代谢组学以及线粒体内代谢示踪， 创伤性脑损伤这些结果将与NVU的线粒体生物能量学分析一起产生。 件.这些研究将直接使用CNS-Met代谢组学核心提供的资源。P7C3- A20可升高NAD+并在TBI模型中显示出疗效，将与烟酰胺一起给药 NAD+前体monopolytide，以检查恢复代谢改变的治疗效果 功能性成果。这些研究的完成将使人们更好地了解 在轻度TBI后NVU的不同组分中的线粒体功能障碍和代谢物通量， 关于靶向NAD+的病理修饰药物治疗这种疾病的支持性数据。