Reprogramming of glucose metabolism and urea cycle in Long-COVID

项目摘要 本申请是对杜兰国家灵长类动物研究中心P51基本资助的补充申请 （TNPRC），以进一步研究SARS-CoV-2感染后急性后遗症（PASC）。这 该申请提出了一个总体假设，即病毒引起的肠道功能障碍，微生物 易位和下游干扰素信号传导诱导参与的代谢途径的失调， 葡萄糖代谢和肝脏中的尿素循环，后者的功能是从肝脏中清除有毒的氨。 身体我们假设这些改变有助于COVID-19感染的主要致病特征 和PASC，特别是慢性疲劳、神经认知障碍和葡萄糖利用失调 导致2型糖尿病，这增加了以前感染SARS的人的患病率， 二型冠状病毒尿素循环的改变也可能促进与严重SARS-CoV-2相关的凝血障碍 感染在鸟氨酸氨甲酰转移酶患者中观察到血栓形成的倾向 缺乏，尿素循环途径中的一种酶将鸟氨酸转化为瓜氨酸。在我们的 根据初步数据，我们提供了支持性证据，证明重症COVID-19患者的瓜氨酸水平降低。这 应用程序利用我们正在进行的研究PASC在非洲绿色猴提供所有必要的 用于本次调查的样本。此应用程序还利用了COVID-19 NHP协调 在TNPRC的中心，我们和其他三个中心从事长期新冠肺炎研究，并将存款我们的 数据作进一步分析。将在hACE 2转基因小鼠K18中进行额外的治疗研究， 我们的研究小组先前已经发表了一个利用营养补充剂的SARS-CoV-2感染模型， 以及在感染期间恢复代谢功能的化合物。该应用程序代表了一种新的调查， 一个令人兴奋的假设，可能会提供新的见解，新的和有效的治疗策略，SARS- CoV-2感染和PASC。

PROJECT SUMMARY This application is a supplement request to our P51 base grant to Tulane National Primate Research Center (TNPRC) to further the investigation of Post-Acute Sequelae of SARS-CoV-2 infection (PASC). This application proposes to investigate the overarching hypothesis that virus-induced gut dysfunction, microbial translocation and downstream interferon signaling induce dysregulation of metabolic pathways involved in glucose metabolism and the urea cycle in the liver, the latter functioning to remove toxic ammonia from the body. We hypothesize that these alterations contribute to major pathogenic features of CoVID-19 infection and PASC, particularly chronic fatigue, neurocognitive disturbances, and dysregulation of glucose utilization contributing to type 2 diabetes, which has increased prevalence in persons previously infected with SARS- CoV-2. Alterations in the urea cycle may also promote clotting disorders associated with severe SARS-CoV-2 infection. Predisposition to thrombus formation has been observed in persons with ornithine transcarbamylase deficiency, an enzyme within the urea cycle pathway converting ornithine to citrulline. Indeed, in our preliminary data, we present supportive evidence of reduced citrulline levels in severe CoVID-19 patients. This application leverages our ongoing studies PASC in the African green monkey providing all the necessary samples for this investigation. This application also takes advantage of the CoVID-19 NHP Coordinating Center at TNPRC where we and three other Centers are engaged in Long-CoVID studies and will deposit our data for further analysis. Addition therapeutic studies will be performed in hACE2 transgenic mice, K18, which our team has published on previously as a model for SARS-CoV-2 infection, utilizing nutritional supplements and compounds to restore metabolic function during infection. This application represents a novel inquiry into an exciting hypothesis that may provide new insights into novel and effective therapeutic strategies for SARS- CoV-2 infection and PASC.