Proteome wide identification of clinically-relevant carbon dioxide targets

背景科学共识认为，往好了说，二氧化碳是一种相对惰性的代谢副产品，往坏了说，二氧化碳是一种有毒分子，如果调节失调，会产生严重的临床后果。然而，临床观察表明，在某些情况下，升高的二氧化碳分压对患者可能是有益的。研究二氧化碳生理效应的分子机制具有临床价值。一项大型队列研究(肺安全，NCT02010073)和对急性呼吸窘迫综合征网络的回顾分析表明，二氧化碳分压升高具有潜在的治疗益处。然而，二氧化碳浓度升高也会对肺(肺泡液清除和上皮细胞修复)、骨骼肌、先天免疫和宿主防御产生有害的病理生理影响。了解二氧化碳的治疗潜力需要了解其传感器。我们已经建立了两种识别二氧化碳靶蛋白的方法，实验和计算。我们已经部署了实验方法来识别二氧化碳结合蛋白，并研究二氧化碳的治疗潜力。我们已经将组蛋白确定为二氧化碳的靶标，并证明了在转录控制中，二氧化碳修饰针对乙酰化/甲基化的赖氨酸。本研究将1.研究组蛋白被二氧化碳修饰的生物医学后果，以揭示二氧化碳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更多二氧化碳目标研究计划众所周知，高碳酸血症针对的是Wnt信号通路，而Wnt失调与包括癌症和心血管疾病在内的一系列疾病有关。这项研究计划分为实验流(四年)和计算流(一年)。实验流将解决以下假设：高碳酸血症通过改变组蛋白靶标从而改变WNT靶基因产物的产生来影响WNT信号。计算流将使用计算方法来识别人类蛋白质组中所有的CO2结合部位，重点放在WNT信号通路中的靶标上。第一个检测组蛋白的CO2体外结合；第二个检测组蛋白的CO2结合

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