Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship

婴儿体外循环中的碱性磷酸酶：动力学和关系

• 批准号: 9520395
• 负责人: Jesse Davidson
• 金额: $ 16.58万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-21 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9520395
• 关键词: Adenine Nucleotides; Adenosine; Adenosine Monophosphate; Adult; Age; Alkaline Phosphatase; Animals; Attenuated; Biological Markers; Cardiac Surgery procedures; Cardiopulmonary Bypass; Cessation of life; Child; Childhood; Clinical; Clinical Research; Clinical Sciences; Cohort Studies; Congenital Abnormality; Congenital Cardiovascular Abnormality; Congenital Heart Defects; Coronary Artery Bypass; Data; Defect; Development Plans; Doctor of Philosophy; Drug Metabolic Detoxication; Endotoxemia; Endotoxins; Enzymes; Excision; Future; Heart Arrest; Heart Diseases; Heart Injuries; Hour; Infant; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intestines; Ischemia; Kinetics; Lead; Lipopolysaccharides; Measurement; Measures; Mechanics; Nitric Oxide Synthase; Nucleotides; Operative Surgical Procedures; Organ; Outcome; Patients; Physiological; Pilot Projects; Population; Postoperative Period; Production; Prognostic Marker; Protein Dephosphorylation; Protein Isoforms; Proteins; Publishing; Recovery; Reperfusion Injury; Reperfusion Therapy; Research; Research Design; Research Project Grants; Risk; Role; Sampling; Serum; Signal Transduction; Systemic Inflammatory Response Syndrome; Techniques; Therapeutic Agents; Therapeutic Intervention; Time; Translational Research; base; career development; clinical risk; cytokine; diagnostic biomarker; extracellular; falls; high risk; improved; improved outcome; inhibitor/antagonist; inorganic phosphate; interest; novel; operation; patient population; predictive marker; primary outcome; procalcitonin; programs; protective effect; public health relevance; repaired; secondary outcome; skills; therapeutic target; translational study

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.

描述(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)手术修复。不幸的是，体外循环导致全身紊乱，可能导致器官损伤或死亡。损伤风险的标记物和改善CPB相关损伤预后的干预措施有限。碱性磷酸酶(AP)可能通过多种机制对CPB损伤起到保护作用。然而，在婴儿体外循环后，AP活性显著下降，术后AP活性低与术后支持需求增加独立相关。还需要进一步的研究来了解AP在婴幼儿CPB中的作用，它作为术后风险的标志的使用，以及它作为治疗剂的潜在价值。这个K23项目将婴儿体外循环后低AP活动的研究与Davidson博士的职业发展目标结合在一起，最终为Davidson博士为未来旨在改善婴儿CPB后预后的AP治疗的独立研究做好准备。总体假设：婴儿体外循环后AP活性低会增加炎症、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 在体外循环诱导的缺血再灌注损伤中，将有害的胞外腺嘌呤核苷酸转化为腺苷。建议：对120天龄的接受CPB的婴儿进行观察性队列研究，测量CPB前、中、后的总AP活性和异构体特异性AP活性。主要结果：AP活性为D80U/L与80U/L的婴儿心脏骤停、机械循环支持或死亡的风险。次要结果：手术后支持需求，器官损伤/炎症的生物标志物。CPB前和CPB后的血清样本将被分析其将一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：证明低AP活性的CPB术后婴儿死亡、心脏骤停或机械循环支持、内毒素血症和炎症/器官损伤的风险更高。2)动力学：测定CPB后AP异构体特异性活性的丢失、恢复及机制。3)机制：测定体外循环前后血清中AP将一磷酸腺苷转化为腺苷的差异能力，并证明外源性AP挽救这一功能的能力。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，向独立研究过渡。2)翻译研究目标：提高基础/翻译研究设计、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博士课程。潜在影响：这项研究的结果将充分确立AP作为一种新的预测生物标记物在这一人群中的作用，提高对婴儿体外循环后AP的生理作用的理解，并有助于指导旨在改善儿童心脏手术后预后的AP治疗的未来研究。

项目成果

Serum metabolic profile of postoperative acute kidney injury following infant cardiac surgery with cardiopulmonary bypass.

• DOI: 10.1007/s00467-021-05095-8
• 发表时间: 2021-10
• 期刊: Pediatric nephrology (Berlin, Germany)
• 作者: Davidson JA;Frank BS;Urban TT;Twite M;Jaggers J;Khailova L;Klawitter J
• 通讯作者: Klawitter J

Alkaline Phosphatase in Infant Cardiopulmonary Bypass: Kinetics and Relationship to Organ Injury and Major Cardiovascular Events.

• DOI: 10.1016/j.jpeds.2017.07.035
• 发表时间: 2017-11
• 期刊: The Journal of pediatrics
• 作者: Davidson JA;Urban TT;Baird C;Tong S;Woodruff A;Twite M;Jaggers J;Simões EAF;Wischmeyer P
• 通讯作者: Wischmeyer P

Interstage Single Ventricle Heart Disease Infants Show Dysregulation in Multiple Metabolic Pathways: Targeted Metabolomics Analysis.

• DOI: 10.1016/j.jacadv.2022.100169
• 发表时间: 2023-01-01
• 期刊: JACC. Advances
• 作者: Frank, Benjamin S;Khailova, Ludmila;Davidson, Jesse A
• 通讯作者: Davidson, Jesse A

Endothelin-1 activation in pediatric patients undergoing surgical coarctation of the aorta repair.

• DOI: 10.4330/wjc.v9.i12.822
• 发表时间: 2017-12-26
• 期刊: World journal of cardiology
• 影响因子: 1.9
• 作者: Frank BS;Urban TT;Tong S;Cassidy C;Mitchell MB;Nichols CS;Davidson JA
• 通讯作者: Davidson JA

Alterations in Metabolites Associated with Hypoxemia in Neonates and Infants with Congenital Heart Disease.

• DOI: 10.32604/chd.2020.012219
• 发表时间: 2020-09-07
• 期刊: Congenital heart disease
• 影响因子: 0.3
• 作者: Pagano E;Frank B;Jaggers J;Twite M;Urban TT;Klawitter J;Davidson J
• 通讯作者: Davidson J