Spinal cord injury causes liver pathology and metabolic dysfunction

与普通人群相比，脊髓损伤(SCI)患者的寿命显著缩短。 30年来从未改变过的统计数据。其中一个原因是“内分泌、代谢和营养疾病”。 SCI人群正以惊人的速度增长(2019 Models Systems报告)。SCI证明了这一点。 代谢综合征(METS)患病率增加的个人，其并发症使他们处于 与普通人群相比，患糖尿病、心血管疾病和中风的风险更高。一个中环 非酒精性脂肪性肝炎的肝脏病理表现是蛋氨酸的特点和致病因素 (NASH)，一种严重的非酒精性脂肪性肝病(NAFLD)。NASH包括肝脏脂肪堆积 (脂肪变性)和炎症，进而导致肝细胞损伤和促炎因子的释放 调解人。NASH可能促进了脊髓损伤后随后的全系统病理。此提案中的实验 旨在确定在急性和慢性脊髓损伤中启动和维持NASH的机制。重点将放在 增加对肝脏的交感神经输入，以及随之而来的肝脏细胞内变化 炎症和脂肪堆积。我们推测脊髓损伤后过多的交感神经输入到肝脏 启动包括TNFa和NFkB在内的促炎级联反应，进而启动肝脏脂肪 积聚和长时间的炎症。我们将使用转基因小鼠技术以及无偏见的- 组学方法全面识别脊髓损伤引起的肝脏细胞变化 “神经性”NASH和METS的后续特征。我们的长期目标是确定治疗靶点 可以阻断脊髓损伤后功能障碍的脊髓/肝轴，恢复肝脏内环境平衡，全面改善 新陈代谢健康。

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.