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: 9320760
• 负责人: Jesse Davidson
• 金额: $ 16.91万
• 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/9320760
• 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; Sepsis Syndrome; Serum; Signal Transduction; 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（由申请人提供）：问题：先天性心脏缺陷通常需要通过心肺旁路（CPB）进行手术修复。不幸的是，CPB会导致全身性危险，可能导致器官损伤或死亡。受伤风险和改善CPB相关遭受损害结果的干预措施的标志是有限的。碱性磷酸酶（AP）可以通过多种机制预防CPB损伤。然而，AP活性在婴儿CPB之后大大降低，术后AP活性低，与术后支持的增加有关。需要进行其他研究来了解AP在婴儿CPB中的作用，其用作术后风险的标志及其作为治疗剂的潜在价值。这个K23项目结合了婴儿CPB后低AP活动的研究与戴维森博士的职业发展目标，最终为Davidson博士准备了未来的独立研究AP疗法研究，旨在改善婴儿CPB后的结果。总体假设：婴儿CPB后的较低AP活性增加了炎症，器官损伤和心脏骤停的风险，机械循环支持或死亡，部分原因是能力降低 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换为腺苷。提案：120个婴儿D120天生的观察队列研究，正在接受CPB的年龄，并在CPB之前，期间和之后测量总特异性AP活性。主要结果：AP活性D80 U/L对> 80 U/L的婴儿心脏骤停，机械循环支持或死亡的风险。次要结果：术后支持要求，器官损伤/炎症的生物标志物。将对CPB前和后血清样品进行分析，以将其单磷酸腺苷转化为腺苷的能力。拟议的研究项目的具体目的：1）临床：证明死亡，心脏骤停或机械循环支持，内毒素血症和炎症/器官损伤的较高风险在AP活性较低的CPB婴儿中。 2）动力学：测量CPB后AP同工型特异性活性损失，恢复和机制。 3）机制：确定CPB血清中AP的差异能力将单磷酸腺苷转化为腺苷，并证明使用外源性AP挽救此功能的能力。职业发展计划的具体目的：1）临床研究目的：提高临床研究技能，使其过渡到独立研究。 2）翻译研究目的：提高基本/转化研究设计，技术和分析的技能。 3）学术目标：完成临床科学计划的硕士学位和博士学位的启动。程序。潜在的影响：这项研究的结果将在该人群中充分确定AP作为一种新型的预测生物标志物，改善对婴儿CPB后AP的生理作用的理解，并有助于指导对AP治疗的未来研究，旨在改善儿科心脏手术后的结局。