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 25%的先天性心脏病(CHD)儿童在出生第一年就接受了干预， 通常需要进行体外循环(CPB)手术。CPB及其相关技术，包括深度 低温停循环是必要的，但会导致术后生理状况不佳。死亡率 对于高风险手术，保证金仍为10%。在这些复杂的手术中，30%会出现重大并发症， 住院时间(LOS)和成本的关键驱动因素。新的诊断、机械和治疗方法 迫切需要采取措施来影响我们的婴儿、家庭和医疗保健系统的这一负担。 代谢物是基因组的小分子最终产物，它们共同决定着每一分钟 细胞生理学。个体代谢物(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变化仍然知之甚少。最近， 接受体外循环的婴儿的代谢特征在最初的24小时内发生了显著变化。 术后两个相关途径(犬尿氨酸和烟酰胺代谢)的代谢物 与死亡率和重症监护室死亡有关。术后24小时和24小时后代谢谱的演变 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：婴幼儿体外循环心脏手术可引起循环代谢的病理改变 跨越多个关键的代谢途径。这些变化直接影响术后结果和器官。 通过有益的代谢物消耗和病理性代谢物的产生相结合而造成的伤害。 建议：这项研究将采用临床和翻译相结合的方法。临床部门将由一个 采用系列靶向代谢特征和途径的婴儿体外循环前瞻性队列研究 术后72小时标测。互补的平移臂将由一个小猪模型组成 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流量。 具体目标1：验证术后24小时代谢特征与综合结果的相关性 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小时的代谢情况。 具体目标2：依次进行犬尿氨酸和烟酰胺代谢途径的定量测绘 A)量化个体代谢物异常，b)确定途径酶的促成变化，以及c) 确定特定通路异常与术后结果的关系。 具体目标3：在体外循环和深低温停循环的仔猪模型中，定量测定循环和器官特异性的犬尿氨酸和 烟酰胺途径的代谢物，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性吲哚胺2，3-双加氧酶抑制。