Neonatal and Pediatric Platelet Function and Pharmacology

新生儿和儿童血小板功能和药理学

• 批准号: 9103240
• 负责人: SCOTT L DIAMOND
• 金额: $ 51.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103240
• 关键词: Address; Adhesions; Adult; Age; Agonist; Animal Model; Antiplatelet Drugs; Arterial Injury; Aspirin; Biochemical; Biological; Biological Assay; Blood; Blood Platelets; Blood Vessels; Cardiac; Caring; Child; Childhood; Clinical Trials; Complex; Congenital Heart Defects; Critical Illness; Deposition; Development; Diagnostic tests; Diamond; Disease; Dose; Drug Monitoring; Drug effect disorder; Enrollment; Epidemic; Event; FDA approved; Future; Health; Heart; Human; In Vitro; Infant; Knowledge; Lead; Lesion; Life; Light; Limb structure; Measures; Mediating; Microfluidic Microchips; Microfluidics; Mission; Monitor; Neonatal; Operative Surgical Procedures; Oral; Pathway interactions; Patient risk; Patients; Pharmaceutical Preparations; Pharmacology; Population; Prevention; Production; Public Health; Pulmonary artery structure; Repair Complex; Research; Risk; Scanning; Second Messenger Systems; Shunt Device; Signal Pathway; Signal Transduction; Site; Staging; Stimulus; Surface; System; Techniques; Technology; Therapeutic; Thrombosis; Thrombus; Translations; Transplanted tissue; Work; age group; age related; base; clinically relevant; clopidogrel; cohort; congenital heart disorder; design; drug development; drug efficacy; falls; high throughput screening; in vitro Assay; in vivo; inhibitor/antagonist; injured; neonate; novel; palliative; patient population; pediatric patients; prevent; release of sequestered calcium ion into cytoplasm; response; second messenger; tertiary care

 DESCRIPTION (provided by applicant): Arterial thromboembolic disease is rapidly becoming the new epidemic of pediatric tertiary care centers due to an increase in invasive monitoring, life saving technologies such as ECMO, and new surgical techniques and graft materials used to repair complex congenital heart lesions. Yet, therapeutic options for preventing or treating this life and limb threatening disorder are limited. Major obstacles to drug development include: (i) A deficiency in knowledge of the extent to which platelets from neonates, infants, and children can form thrombi in injured blood vessels, (ii) limited information on the ability of various agents to curtail pediatric platelet- mediated adhesion and activation under physiologically relevant conditions, and (iii) a lack of sophisticated technologies that permit rapid assessment of pediatric platelet responses to agonists and antagonists in a high-throughput manner using a minimum quantity of blood. To address these clinically relevant issues, low volume microfluidic devices and high throughput screens (HTS) will be used to predict platelet responses to multiple combinations of agonists as well as antagonists, while a novel biological platform will be used for the in vivo assessment of drug efficacy in the prevention of pediatric platelet-mediated thrombosis. Critical questions to be addressed include: Can sophisticated technologies be developed that permit rapid assessment of pediatric platelet responses to agonists and antagonists in a high- throughput manner using a minimum quantity of blood? Can novel agents be identified for future development or use? Are there age related differences in function that would preclude the use of specific anti-platelet agents in certain subsets of pediatric patients? Can a small animal model be developed to better assess pediatric platelet responses to anti-thrombotic agents? Can in vitro assays be predictive of drug efficacy in vivo? Ultimately, we believe the work outlined in this proposal will lead to a better understanding of the appropriate class of anti-platelet agent to use for at risk pediatric patients. Moreover, it may be possible to define the feasibility and enrollment criteria for future clinical trials to test the diagnostic utlity of our in vitro approaches. The proposed work is also relevant to the mission of the agency, which is to encourage translational and collaborative research to advance our knowledge of underlying mechanisms of drug action and response in children at various developmental stages.

 描述（由应用提供）：由于侵入性监测，生命的增加，动脉血栓栓塞疾病正迅速成为小儿三级护理中心的新流行病 节省ECMO等技术，以及用于修复复杂先天性心脏病变的新型手术技术和移植物材料。然而，预防或治疗这种生命和肢体威胁障碍的治疗选择是有限的。药物开发的主要障碍包括：（i）缺乏知识的知识，来自新生儿，婴儿和儿童的血小板在多大程度上可以在受伤的血管中形成血栓，（ii）有关各种药物能力的信息有限 在物理相关的条件下减少小儿血小板介导的粘合剂和激活，以及（iii）缺乏精致的技术，这些技术允许使用最小的血液以高通量方式快速评估对激动剂和拮抗剂的小儿血小板反应。为了解决这些临床相关问题，低体积的微流体设备和高吞吐量筛选（HTS）将用于预测血小板对激动剂和拮抗剂多种组合的响应，而新型的生物学平台将用于对药物效率的体外评估，以预防儿童骨骼介导的肌肉介导的肌肉介导的肌肉发作。要解决的关键问题包括：是否可以开发复杂的技术，以便使用最少的血液以高通量方式快速评估小儿血小板对激动剂和激动剂的反应？可以确定新颖的代理商以供未来开发或使用吗？是否存在与年龄相关的功能差异，这将排除在小儿患者某些子集中使用特定抗血小板药物的使用？可以开发小动物模型来更好地评估小儿血小板对抗栓性药物的反应吗？体外测定可以预测体内药物效率吗？最终，我们认为该提案中概述的工作将使对适用于AT风险的小儿患者使用的适当类抗原剂剂有更好的了解。而且，可能有可能 定义未来临床试验的可行性和入学标准，以测试我们体外方法的诊断效用。拟议的工作也与该机构的使命有关，这是为了鼓励翻译和协作研究，以促进我们对各个发育阶段儿童毒品行动和反应的潜在机制的了解。