Integrated systems biology of multiple organ dysfunction in acute pancreatitis

急性胰腺炎多器官功能障碍的综合系统生物学

• 批准号: 1805067
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1805067
• 关键词: Integrated; systems; biology; multiple; organ

Acute pancreatitis (AP) is an inflammatory condition of the pancreas. Main identified causes are gallstones and alcohol abusive consumption. It can lead, in 20% of the cases, to multiple organ dysfunction syndrome (MODS) requiring the admission to an intensive care unit and causing death in approximately 20% of the cases. At the time there is no specific therapy to treat AP or to prevent AP-MODS. Care currently provided to patients with AP is solely supportive and thus constitutes a crucial need to address. Recently, an enzyme (Kynurenine-3-monooxygenase), part of the kynurenine pathway and involved in tryptophan metabolism, has been identified as playing a key role in AP-MODS. On mice with no KMO activity, when AP was induced, lungs, liver and kidneys were protected from being damaged. In this context an inhibitor of KMO has been developed and is aimed at producing a similar effect on patients with AP. Currently, there is no way of predicting MODS during AP, thus it is not possible to predict which patients could actually benefit from this new therapeutic strategy. In this context, seventy-nine patients presenting AP were recruited from the Royal Infirmary of Edinburgh. For this cohort, metabolomics profiling, RNA-sequencing and clinical data collection were performed at different time points using blood samples. This comprehensive dataset could be used to try to stratify the cohort in order to identify subgroups that could benefit from the new potential medicine as well as identifying shared features that could help in understanding AP biology better. Outcome prediction is also important to perform as it has the potential to help anticipating MODS. Therapeutic targets could as well be identified using data-analysis methods and find relevant elements that could be investigated further as treatment targets.

急性胰腺炎（AP）是胰腺的炎症性疾病。主要确定的原因是胆结石和酗酒。 20% 的病例可能会导致多器官功能障碍综合征 (MODS)，需要进入重症监护室，并导致大约 20% 的病例死亡。目前尚无治疗 AP 或预防 AP-MODS 的特异性疗法。目前向 AP 患者提供的护理仅是支持性的，因此构成了迫切需要解决的问题。最近，一种酶（Kynurenine-3-monooxygenase）是犬尿氨酸途径的一部分，参与色氨酸代谢，已被确定在 AP-MODS 中发挥关键作用。在没有 KMO 活性的小鼠中，当诱导 AP 时，肺、肝脏和肾脏受到保护，免受损害。在此背景下，KMO 抑制剂已被开发出来，旨在对 AP 患者产生类似的效果。目前，尚无方法预测 AP 期间的 MODS，因此无法预测哪些患者实际上可以从这种新的治疗策略中受益。在此背景下，从爱丁堡皇家医院招募了 79 名出现 AP 的患者。对于该队列，在不同时间点使用血液样本进行代谢组学分析、RNA 测序和临床数据收集。这个综合数据集可用于尝试对队列进行分层，以确定可以从新的潜在药物中受益的亚组，并确定有助于更好地理解 AP 生物学的共同特征。结果预测也很重要，因为它有可能帮助预测 MODS。也可以使用数据分析方法来确定治疗目标，并找到可以作为治疗目标进一步研究的相关元素。

项目成果

Quantitative magnetic resonance imaging predicts individual future liver performance after liver resection for cancer.

定量磁共振成像可以预测肝切除癌后个体未来的肝脏表现。

• DOI: 10.1371/journal.pone.0238568
• 发表时间: 2020
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Mole DJ;Fallowfield JA;Sherif AE;Kendall T;Semple S;Kelly M;Ridgway G;Connell JJ;McGonigle J;Banerjee R;Brady JM;Zheng X;Hughes M;Neyton L;McClintock J;Tucker G;Nailon H;Patel D;Wackett A;Steven M;Welsh F;Rees M;HepaT1ca Study Group
• 通讯作者: HepaT1ca Study Group

Multiomic definition of generalizable endotypes in human acute pancreatitis

人类急性胰腺炎普遍内型的多组学定义

• DOI: 10.1101/539569
• 发表时间: 2019
• 作者: Neyton L

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

• DOI: 10.1371/journal.pcbi.1005934
• 发表时间: 2018-03
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Baillie JK;Bretherick A;Haley CS;Clohisey S;Gray A;Neyton LPA;Barrett J;Stahl EA;Tenesa A;Andersson R;Brown JB;Faulkner GJ;Lizio M;Schaefer U;Daub C;Itoh M;Kondo N;Lassmann T;Kawai J;IIBDGC Consortium;Mole D;Bajic VB;Heutink P;Rehli M;Kawaji H;Sandelin A;Suzuki H;Satsangi J;Wells CA;Hacohen N;Freeman TC;Hayashizaki Y;Carninci P;Forrest ARR;Hume DA
• 通讯作者: Hume DA

Kynurenine monooxygenase regulates inflammation during critical illness and recovery in experimental acute pancreatitis

犬尿氨酸单加氧酶调节实验性急性胰腺炎危重病和恢复期间的炎症

• DOI: 10.1016/j.hpb.2020.11.549
• 发表时间: 2021
• 期刊: HPB
• 影响因子: 2.9
• 作者: Hayes A