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170万个脑损伤， 其中约80%是轻微的，在美国每年都有报道。脑外伤也是痴呆症的主要危险因素 阿尔茨海默氏症。轻度颅脑损伤的特点是神经血管单位(NVU)功能障碍，由 血脑屏障破裂，紧随其后的是突触运动失调。线粒体功能障碍是 轻度颅脑损伤后NVU表现明显，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 TBI。这些结果将与NVU的线粒体生物能量学特征相结合产生 组件。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+，并在脑损伤模型中证明其有效性，将与烟酰胺一起使用 作为NAD+前体的单核苷酸，用于检测恢复代谢变化的疗效 和功能结果。这些研究的完成将加深对 轻度颅脑损伤后NVU不同部分的线粒体功能障碍和代谢产物流量 针对NAD+治疗这种疾病的病理修改药物的支持性数据。