Spinal cord injury causes liver pathology and metabolic dysfunction

脊髓损伤导致肝脏病理和代谢功能障碍

• 批准号: 10589087
• 负责人: DANA M MCTIGUE
• 金额: $ 53.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589087
• 关键词: Acute; Adrenergic Agents; Autonomic nervous system; Biological Models; Cardiovascular Diseases; Cause of Death; Cells; Central obesity; Ceramides; Chronic; Complex; Data; Development; Disease; Disinhibition; Dyslipidemias; Eating; Endocrine; Enzymes; Fatty acid glycerol esters; General Population; Genetic; Genetic Transcription; Goals; Health; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Hyperactivity; Hyperglycemia; Hypertension; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Insulin Resistance; Interruption; Intervention; Kupffer Cells; Link; Lipids; Liver; Liver diseases; Liver neoplasms; Liver parenchyma; Longevity; Mediator; Metabolic; Metabolic dysfunction; Metabolic syndrome; Molecular Target; Morbidity - disease rate; NF-Kappa B p65; NF-kappa B; Neurons; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Nutritional and Metabolic Diseases; Obesity; Operative Surgical Procedures; Organ; Pathology; Pathway interactions; Play; Population; Prevalence; Rattus; Recovery; Reporting; Risk; Rodent; Role; Signal Induction; Signal Transduction; Spinal Cord; Spinal cord injury; Stroke; Sympathectomy; Sympathetic Nervous System; System; Systemic disease; TNF gene; Technology; Testing; Transgenic Mice; Transgenic Organisms; Work; cardiometabolic risk; cell injury; design; designer receptors exclusively activated by designer drugs; diabetes risk; experimental study; high risk; improved; insight; lipid metabolism; lipidomics; liver function; liver inflammation; mouse genetics; negative affect; neurological recovery; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; pre-clinical; sedentary lifestyle; serine palmitoyltransferase; single-cell RNA sequencing; statistics; therapeutic target

Spinal cord injured (SCI) individuals have significantly reduced lifespans compared to the general population, a statistic that has not changed in 30 years. One reason is “endocrine, metabolic and nutritional diseases”, which are increasing at alarming rates in the SCI population (2019 Models Systems report). This is evidenced by SCI individuals having increased prevalence of Metabolic Syndrome (MetS), the complications of which put them at a higher risk for diabetes, cardiovascular disease and stroke compared to the general population. A central feature of MetS and contributor to morbidity is hepatic pathology in the form of non-alcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD). NASH includes hepatic lipid accumulation (steatosis) and inflammation, which in turn cause hepatocyte damage and release of pro-inflammatory mediators. NASH likely facilitates subsequent systems-wide pathology after SCI. Experiments in this proposal are designed to identify mechanisms that initiate and sustain NASH in acute and chronic SCI. Focus will be on increased sympathetic input to the liver and consequent intracellular changes in the liver that drive inflammation and fat accumulation. We hypothesize that excess sympathetic input to the liver after SCI initiates pro-inflammatory cascades involving TNFa and NFkB, which in turn initiate hepatic fat accumulation and prolonged inflammation. We will use transgenic mouse technology as well as unbiased - omics approaches to comprehensively identify cellular changes in the liver induced by SCI that drive “neurogenic” NASH and subsequent features of MetS. Our long-term goal is to identify therapeutic targets that can interrupt the dysfunctional spinal cord/liver axis after SCI to restore liver homeostasis and improve overall metabolic health.

与一般人群相比 统计数据在30年内没有改变。原因之一是“内分泌，代谢和营养疾病”，这是 SCI人群的惊人速度正在增加（2019年模型系统报告）。科学证明了这一点 具有代谢综合征（MetS）患病率增加的人，其并发症使他们处于 与普通人群相比，糖尿病，心血管疾病和中风的风险更高。中央 Mets的特征和发病率的贡献者是肝病病理学，以非酒精性脂肪性肝炎的形式形式 （NASH），一种严重的非酒精性脂肪肝病（NAFLD）。纳什包括肝脂质积累 （脂肪变性）和炎症，进而导致肝细胞损害和促炎性炎症 调解人。纳什的可能性最爱随后在SCI后随后全系统病理。该提案中的实验 旨在识别启动和维持急性和慢性科学纳什的机制。重点将开始 增加对肝脏的交感神经输入以及随之而来的肝内细胞内变化 炎症和脂肪积累。我们假设这超过了SCI后对肝脏的交感神经输入 启动涉及TNFA和NFKB的促炎性级联 积累和长时间的炎症。我们将使用转基因小鼠技术以及公正 - OMICS的方法是全面识别SCI诱导的肝脏的细胞变化 “神经源性” NASH和随后的Mets特征。我们的长期目标是确定治疗目标 SCI后可以中断功能失调的脊髓/肝轴，以恢复肝稳态并改善整体 代谢健康。