Spinal cord injury causes liver pathology and metabolic dysfunction

与一般人群相比，脊髓损伤（SCI）患者的寿命显著缩短， 30年来没有变化的统计数据。原因之一是“内分泌、代谢和营养疾病”， 在SCI人群中以惊人的速度增长（2019年模型系统报告）。这一点，SCI 代谢综合征（MetS）患病率增加的个体，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较高。中央 MetS的一个特征和致病因素是非酒精性脂肪性肝炎形式的肝脏病理学 NASH是一种严重的非酒精性脂肪肝（NAFLD）。NASH包括肝脏脂质蓄积 脂肪变性和炎症，这反过来又导致肝细胞损伤和促炎性细胞因子的释放。 调解员NASH可能促进SCI后随后的系统范围病理学。本提案中的实验 旨在确定在急性和慢性SCI中启动和维持NASH的机制。重点将是 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， 启动涉及TNF α和NF κ B的促炎级联反应，进而启动肝脂肪 积累和长期炎症。我们将使用转基因老鼠技术以及无偏见的- 组学方法来全面识别SCI诱导的肝脏细胞变化， “神经源性”NASH和MetS的后续特征。我们的长期目标是确定治疗靶点， 可以中断SCI后功能失调的脊髓/肝轴，以恢复肝脏稳态， 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.