Neonatal and Pediatric Platelet Function and Pharmacology

 描述(申请人提供)：动脉血栓栓塞症正在迅速成为儿科三级护理中心的新流行病，因为侵入性监测、LIFE的增加 节省ECMO等技术，以及用于修复复杂先天性心脏病病变的新外科技术和移植材料。然而，预防或治疗这种威胁生命和肢体的疾病的治疗选择是有限的。药物开发的主要障碍包括：(I)缺乏对新生儿、婴儿和儿童的血小板在受损血管中形成血栓的程度的了解；(Ii)关于各种制剂作用能力的信息有限 (3)缺乏先进的技术，可以用最少的血液以高通量的方式快速评估儿童血小板对激动剂和拮抗剂的反应。为了解决这些临床相关问题，将使用低容量微流控设备和高通量筛选(HTS)来预测血小板对多种激动剂和拮抗剂组合的反应，而一个新的生物平台将用于体内评估预防儿童血小板介导的血栓形成的药物疗效。需要解决的关键问题包括：能否开发尖端技术，用最少的血液以高通量的方式快速评估儿科血小板对激动剂和拮抗剂的反应？能否为未来的开发或使用确定新的试剂？是否存在年龄相关的功能差异，从而排除了在某些儿科患者中使用特定抗血小板药物的可能性？能否开发一种小动物模型来更好地评估儿童血小板对抗血栓药物的反应？体外试验能预测体内的药物疗效吗？最终，我们相信，这项提案中概述的工作将使我们更好地理解用于高危儿科患者的适当类别的抗血小板药物。此外，还有可能 确定未来临床试验的可行性和登记标准，以测试我们体外方法的诊断实用性。拟议的工作也与该机构的使命有关，即鼓励翻译和合作研究，以增进我们对儿童不同发育阶段药物作用和反应的潜在机制的了解。

 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.