Proteome wide identification of clinically-relevant carbon dioxide targets

背景科学共识认为，二氧化碳，在最好的情况下，一个相对惰性的代谢副产品，在最坏的情况下，一个有毒的分子与严重的临床后果，如果失调。然而，临床观察表明，在某些情况下，PCO 2升高可能对患者有益，因此，研究CO2生理效应的分子机制具有临床价值。一项大型队列研究（LUNG SAFE，NCT 02010073）和急性呼吸窘迫综合征网络的回顾性分析证明了PCO 2升高的潜在治疗获益。然而，升高的PCO 2也会对肺（肺泡液清除和上皮细胞修复）、骨骼肌和先天免疫以及宿主防御产生有害的病理生理学影响。了解CO2的治疗潜力需要了解其传感器。我们建立了两种鉴定CO2靶蛋白的实验方法和计算方法，并将实验方法用于鉴定CO2结合蛋白和研究CO2的治疗潜力。我们已经确定组蛋白作为CO2的目标，并证明CO2修改赖氨酸靶向乙酰化/甲基化的转录控制。这份奖学金将1。研究CO2修饰组蛋白的生物医学后果，揭示PCO 2在临床上的治疗潜力.部署计算以揭示人类蛋白质组中可能影响这些过程的进一步CO2靶点研究计划已知高碳酸血症靶向Wnt信号通路，Wnt失调与一系列疾病有关，包括癌症和心血管疾病。研究计划分为实验组（四年）和计算流实验流程将解决高碳酸血症通过修饰组蛋白靶点从而改变Wnt的产生来影响Wnt信号传导的假设。计算流将使用计算方法来鉴定人类蛋白质组中的所有CO2结合位点，重点是Wnt信号传导中的靶标。第一个检查组蛋白CO2结合在体外;第二个检查组蛋白CO2结合在体外。

BackgroundScientific consensus has considered CO2, at best, a relatively inert metabolic by-product, and at worst, a toxic molecule with severe clinical consequences if dysregulated. However, clinical observations demonstrate elevated PCO2 might be beneficial to patients in certain circumstances.There is clinical value in addressing the molecular mechanisms for the physiological effects of CO2. A large cohort study (LUNG SAFE, NCT02010073) and retrospective analysis of the Acute Respiratory Distress Syndrome Network demonstrated the potential therapeutic benefit of elevated PCO2. However, elevated PCO2 can also have harmful pathophysiological effects on the lung (alveolar fluid clearance and epithelial cell repair), skeletal muscle and innate immunity and host defence.Understanding the therapeutic potential for CO2 requires knowledge of its sensors. We have established two methodologies for identifying CO2 target proteins, experimental and computational.We have deployed the experimental methodology to identify CO2-binding proteins and investigate the therapeutic potential for CO2. We have identified histones as a CO2 target and demonstrated that CO2 modifies lysine targeted for acetylation/methylation in transcriptional control. This studentship will 1. Investigate the biomedical consequences for histone modification by CO2 to reveal the therapeutic potential for PCO2 in the clinic.2. Deploy computation to reveal further CO2 targets in the human proteome that might impact on these processesResearch PlanHypercapnia is known to target the Wnt signalling pathway and Wnt dysregulation is linked to a range of diseases including cancer and cardiovascular disease. The research plan is split an experimental stream (four years) and a computational stream (one year).The experimental stream will address the hypothesis that hypercapnia impacts Wnt signalling through modifying histone targets thus altering the production of Wnt-target gene products.The computational stream will use a computational approach to identify all CO2 binding sites in the human proteome with an emphasis on targets in the Wnt signalling pathway.The first examines histone CO2-binding in vitro; the second examines histone CO2-binding