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.

项目概要 25% 的先天性心脏病 (CHD) 儿童在生命的第一年接受干预， 通常需要进行体外循环（CPB）手术。 CPB 和相关技术，包括深度 低温停循环（DHCA）是必要的，但会导致术后生理状况不佳。死亡 高风险手术的比例仍>10%。这些复杂手术中 30% 会出现主要并发症 住院时间 (LOS) 和费用的主要驱动因素。新颖的诊断、机制和治疗 迫切需要采取措施来减轻我们的婴儿、家庭和医疗保健系统的负担。 代谢物是基因组的小分子最终产物，它们共同决定着每分钟的生命 细胞生理学。个体代谢物（例如乳酸）通常用于术后管理，但是 婴儿心脏手术引起的相关代谢组变化仍知之甚少。最近， 接受 CPB 的婴儿的代谢特征在最初 24 小时内发生了显着变化 术后和来自两个相关途径（犬尿氨酸和烟酰胺代谢）的代谢物 与死亡率和 ICU LOS 相关。术后 24 小时后代谢特征的演变 循环/组织犬尿氨酸和烟酰胺代谢物的全面变化尚不清楚。 总体假设：婴儿心脏手术联合体外循环会引起循环代谢组的病理变化 跨越多个关键代谢途径。这些变化直接影响术后结果和器官 通过有益代谢物消耗和病理代谢物产生的结合造成损伤。 提案：该研究将采用临床和转化相结合的方法。临床部门将包括 对接受 CPB 的婴儿进行的前瞻性队列研究，包括一系列有针对性的代谢分析和途径 术后 72 小时内进行绘图。互补的平移臂将由一个仔猪模型组成 CPB/DHCA 通过犬尿氨酸和烟酰胺代谢来评估和调节器官特异性通量。 具体目标 1：验证术后 24 小时代谢特征与综合结果的关联 死亡、心脏骤停或机械循环支持，并确定这种病理学的演变 术后 72 小时的代谢情况。 具体目标 2：按顺序对犬尿氨酸和烟酰胺代谢途径进行定量绘图 a) 量化个体代谢异常，b) 确定途径酶的贡献变化，以及 c) 确定特定途径异常与术后结果的关联。 具体目标 3：在采用 DHCA 的 CPB 仔猪模型中，量化循环和器官特异性犬尿氨酸，并 烟酰胺途径代谢并确定途径阻断对发育的影响 术后急性器官损伤采用全身吲哚胺2,3-双加氧酶抑制。