Metabolic profiling and comprehensive metabolic pathway mapping: a systems biology approach to cardiovascular failure and organ injury following infant congenital heart disease surgery

代谢谱和综合代谢途径图谱：婴儿先天性心脏病手术后心血管衰竭和器官损伤的系统生物学方法

• 批准号: 10400930
• 负责人: Jesse Davidson
• 金额: $ 62.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400930
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Affect; Animal Model; Blood Tests; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cardiovascular system; Cell physiology; Cerebrum; Cessation of life; Child; Childhood; Clinical; Complex; Congenital Abnormality; Dangerousness; Data; Development; Evolution; Failure; Family; Genome; Goals; Healthcare Systems; Heart Arrest; Heart failure; Homeostasis; Hospital Costs; Hospitalization; Individual; Infant; Injury to Kidney; Intensive Care Units; Intervention; Kynurenine; Lead; Length of Stay; Life; Live Birth; Maintenance; Measures; Metabolic; Metabolic Pathway; Metabolism; Niacinamide; Operative Surgical Procedures; Organ; Outcome; Pathologic; Pathway interactions; Patients; Perfusion; Physiological; Physiology; Postoperative Period; Production; Prospective cohort study; Proteome; Renal Tissue; Respiratory Failure; Risk; Single ventricle congenital heart disease; Stress; Systems Biology; Techniques; Testing; Therapeutic; Tissues; Tryptophan; Tryptophan 2,3 Dioxygenase; arm; base; cardiovascular collapse; congenital heart disorder; cost; enzyme pathway; experience; high risk; innovation; mechanical circulatory support; metabolic profile; metabolome; metabolomics; mortality; new therapeutic target; novel; novel diagnostics; organ injury; palliation; perioperative mortality; porcine model; response; sex; small molecule; surgical risk; translational approach

Project Summary Twenty-five percent of children with congenital heart disease (CHD) undergo intervention in the first year of life, often requiring surgery with cardiopulmonary bypass (CPB). CPB and related techniques including deep hypothermic circulatory arrest (DHCA) are necessary but contribute to poor postoperative physiology. Mortality for high risk surgeries remains >10%. Major complications occur in 30% of these complex surgeries and are key drivers of hospital length of stay (LOS) and costs. Novel diagnostic, mechanistic, and therapeutic approaches are critically needed to impact this burden on our infants, families, and healthcare system. Metabolites are the small-molecule end products of the genome that collectively determine minute-to-minute cellular physiology. Individual metabolites (e.g. lactate) are commonly used in postoperative management, but the interrelated metabolomic changes induced by infant cardiac surgery remain poorly understood. Recently, the metabolic profile of infants undergoing CPB was shown to shift markedly during the first 24hrs postoperatively and metabolites from two related pathways (kynurenine and nicotinamide metabolism) were associated with mortality and ICU LOS. Evolution of the postoperative metabolic profile beyond 24hrs and comprehensive changes in circulating/tissue kynurenine and nicotinamide metabolites are unknown. Overall Hypothesis: Infant cardiac surgery with CPB induces pathologic changes in the circulating metabolome across multiple key metabolic pathways. These changes directly impact postoperative outcomes and organ injury through a combination of beneficial metabolite depletion and pathologic metabolite production. Proposal: The study will use a combined clinical and translational approach. The clinical arm will consist of a prospective cohort study of infants undergoing CPB, with serial targeted metabolic profiling and pathway mapping through 72hrs postoperatively. The complementary translational arm will consist of a piglet model of CPB/DHCA to evaluate and modulate organ-specific flux through kynurenine and nicotinamide metabolism. Specific Aim 1: Validate the association of the 24hr postoperative metabolic profile with the combined outcome of death, cardiac arrest, or mechanical circulatory support and determine the evolution of this pathologic metabolic profile through 72hrs postoperatively. Specific Aim 2: Perform quantitative mapping of the kynurenine and nicotinamide metabolic pathways in order to a) quantify individual metabolite abnormalities, b) identify contributing changes in pathway enzymes, and c) determine the association of specific pathway abnormalities with postoperative outcomes. Specific Aim 3: In a piglet model of CPB with DHCA, quantify circulating and organ-specific kynurenine and nicotinamide pathway metabolites and determine the effects of pathway blockade on development of postoperative acute organ injury using systemic indoleamine 2,3-dioxygenase inhibition.

项目摘要 先天性心脏病（CHD）的儿童中有25％在生命的第一年接受干预， 通常需要用心肺旁路（CPB）手术。 CPB及相关技术，包括深 低温循环停滞（DHCA）是必要的，但导致术后生理不良。死亡 对于高风险，手术仍> 10％。这些复杂手术中有30％发生了重大并发症， 住院时间长度（LOS）和费用的主要驱动力。新颖的诊断，机械和治疗性 需要采取迫切需要对婴儿，家庭和医疗保健系统的负担。 代谢物是基因组的小分子终极产物，该产品集体确定分钟 细胞生理。单个代谢产物（例如乳酸）通常用于术后管理，但 婴儿心脏手术引起的相互关联的代谢组变化仍然很少了解。最近， 在前24小时内，表现出接受CPB的婴儿的代谢特征明显转移 术后和来自两种相关途径（Kynurenine和Nicotinamide代谢）的代谢产物是 与死亡率和ICU LOS相关。 24小时以上的术后代谢概况的演变和 循环/组织kynurenine和烟酰胺代谢产物的全面变化尚不清楚。 总体假设：CPB的婴儿心脏手术诱导循环代谢组的病理变化 跨多个关键代谢途径。这些变化直接影响术后结果和器官 通过有益的代谢产物耗竭和病理代谢物产生的结合来损伤。 提案：该研究将使用综合的临床和翻译方法。临床部门将由 对接受CPB的婴儿的前瞻性队列研究，具有序列针对的代谢分析和途径 术后绘制72小时。互补的翻译臂将由仔猪模型组成 CPB/DHCA评估和调节器官特异性通量通过Kynurenine和Nicotinamide代谢。 特定目标1：验证24小时术后代谢概况与结合结果的关联 死亡，心脏骤停或机械循环支持，并确定这种病理的演变 术后72小时的代谢剖面。 特定目的2：进行kynurenine和烟酰胺代谢途径的定量映射顺序 a）量化单个代谢产物异常，b）确定途径酶的变化，c） 确定特定途径异常与术后结局的关联。 特定目标3：在具有DHCA的CPB的小猪模型中 烟酰胺途径代谢产物，并确定途径阻塞对发展的影响 术后使用全身性吲哚胺2,3-二加氧酶抑制。