Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship

描述（由申请人提供）： 问题：先天性心脏缺陷通常需要通过体外循环 (CPB) 进行手术修复。不幸的是，体外循环会导致全身紊乱，从而导致器官损伤或死亡。伤害风险标记和改善 CPB 相关伤害结果的干预措施有限。碱性磷酸酶 (AP) 可通过多种机制防止体外循环损伤。然而，婴儿体外循环后 AP 活动大幅下降，并且术后 AP 活动低与术后支持需求增加独立相关。需要进行更多研究来了解 AP 在婴儿 CPB 期间的作用、其作为术后风险标记的用途以及其作为治疗剂的潜在价值。该 K23 项目将婴儿 CPB 后低 AP 活动的研究与戴维森博士的职业发展目标结合起来，最终为戴维森博士做好未来 AP 治疗独立研究的准备，旨在改善婴儿 CPB 后的结果。总体假设：婴儿 CPB 后低 AP 活性会增加炎症、器官损伤、心脏骤停、机械循环支持或死亡的风险，部分原因是婴儿 CPB 后的 AP 活性下降 在 CPB 诱导的缺血再灌注损伤的情况下，将有害的细胞外腺嘌呤核苷酸转化为腺苷。提案：对 120 名 120 天龄接受 CPB 的婴儿进行观察性队列研究，测量 CPB 之前、期间和之后的总 AP 活性和亚型特异性 AP 活性。主要结局：AP 活性为 d80 U/L 与 >80 U/L 的婴儿发生心脏骤停、机械循环支持或死亡的风险。次要结果：术后支持需求、器官损伤/炎症的生物标志物。将分析 CPB 前和后血清样本将单磷酸腺苷转化为腺苷的能力。拟议研究项目的具体目标： 1) 临床：证明 AP 活性较低的 CPB 后婴儿死亡、心脏骤停或机械循环支持、内毒素血症和炎症/器官损伤的风险较高。 2) 动力学：测量体外循环后 AP 亚型特异性活性的丧失、恢复和机制。 3) 机制：确定 CPB 前后血清中 AP 将单磷酸腺苷转化为腺苷的能力差异，并证明外源性 AP 能够挽救这一功能。职业发展计划的具体目标： 1）临床研究目标：提高临床研究技能，过渡到独立研究。 2) 转化研究目标：提高基础/转化研究设计、技术和分析的技能。 3) 学术目标：完成临床科学硕士课程并开始攻读博士学位。程序。潜在影响：本研究的结果将充分确立 AP 作为该人群的新型预测生物标志物，提高对婴儿 CPB 后 AP 生理作用的理解，并有助于指导未来旨在改善小儿心脏手术后结局的 AP 治疗研究。

DESCRIPTION (provided by applicant): Problem: Congenital heart defects often require surgical repair with cardiopulmonary bypass (CPB). Unfortunately CPB causes systemic derangements that can lead to organ injury or death. Markers of injury risk and interventions to improve outcomes from CPB related-injury are limited. Alkaline phosphatase (AP) may protect against CPB injury through multiple mechanisms. AP activity, however, falls substantially following infant CPB and low post-operative AP activity is independently associated with increased post-operative support requirements. Additional research is needed to understand the role of AP during infant CPB, its use as a marker of post-operative risk, and its potential value as a therapeutic agent. This K23 project combines the study of low AP activity after infant CPB with career development aims for Dr. Davidson, ultimately preparing Dr. Davidson for future independent research in AP therapy aimed at improving outcomes after infant CPB. Overall Hypothesis: Low AP activity after infant CPB increases the risk of inflammation, organ injury, and cardiac arrest, mechanical circulatory support, or death, in part due to a decreased ability to convert harmful extracellular adenine nucleotides to adenosine in the setting of CPB induced ischemia-reperfusion injury. Proposal: Observational cohort study of 120 infants d120 days of age undergoing CPB with measurement of total and isoform specific AP activity before, during, and after CPB. Primary outcome: risk of cardiac arrest, mechanical circulatory support, or death in infants with AP activity d80 U/L versus >80 U/L. Secondary outcomes: post-operative support requirements, biomarkers of organ injury/inflammation. Pre and post-CPB serum samples will be analyzed for their ability to convert adenosine monophosphate to adenosine. Specific Aims of the Proposed Research Project: 1) Clinical: Demonstrate a higher risk of death, cardiac arrest, or mechanical circulatory support, endotoxemia, and inflammation/organ injury in post-CPB infants with low AP activity. 2) Kinetics: Measure AP isoform-specific activity loss, recovery, and mechanism following CPB. 3) Mechanism: Determine the differential capacity of AP in pre and post-CPB serum to convert adenosine monophosphate to adenosine and demonstrate the ability to rescue this function with exogenous AP. Specific Aims of the Career Development Plan: 1) Clinical Research Aim: Improve clinical research skills to make the transition to independent research. 2) Translational Research Aim: Improve skills in basic/translational study design, techniques, and analysis. 3) Scholarly Aim: Completion of the Masters of Clinical Science program and initiation of the Ph.D. program. Potential Impact: The results of this study will fully establish AP as a novel predictive biomarker in this population, improve the understanding of the physiologic role of AP after infant CPB, and help direct future studies of AP treatment aimed at improving outcomes after pediatric cardiac surgery.