权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10613465
负责人：
Jesse Davidson
金额：
$ 61.56万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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

项目摘要

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）儿童在出生后第一年接受了干预，经常需要进行心肺转流（CPB）手术。体外循环和相关技术，包括深度低温停循环（DHCA）是必要，但会导致不良的术后生理学。死亡率对于高风险手术，仍保持> 10%。在这些复杂手术中，30%发生严重并发症，住院时间（LOS）和费用的主要驱动因素。新型诊断、机理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。代谢产物是基因组的小分子终产物，它们共同决定着每分钟的细胞生理学单个代谢物（例如乳酸盐）通常用于术后管理，但婴儿心脏手术引起的相关代谢组学变化仍然知之甚少。最近，接受CPB的婴儿的代谢谱在最初的24小时内发生了明显的变化术后，来自两个相关途径（犬尿氨酸和烟酰胺代谢）的代谢物被与死亡率和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未知。总体假设：婴儿心脏手术联合CPB诱导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性代谢物产生的组合造成损伤。建议：本研究将采用临床和转化相结合的方法。临床组将包括采用系列靶向代谢谱和途径对接受CPB的婴儿进行的前瞻性队列研究术后72小时的标测。互补的平移臂将由以下小猪模型组成： CPB/DHCA通过犬尿氨酸和烟酰胺代谢评估和调节器官特异性通量。具体目标1：确定术后24小时代谢特征与综合结局的相关性死亡，心脏骤停，或机械循环支持，并确定这种病理的演变术后72小时的代谢特征。具体目标2：对犬尿氨酸和烟酰胺代谢途径进行定量绘图， a）量化个体代谢物异常，B）鉴定途径酶的贡献变化，和c）确定特定通路异常与术后结局的相关性。具体目标3：在采用DHCA的CPB仔猪模型中，定量循环和器官特异性犬尿氨酸，烟酰胺途径代谢产物，并确定途径阻断对发展的影响，使用全身性吲哚胺2，3-双加氧酶抑制的术后急性器官损伤。