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（由申请人提供）：由于侵入性监测、生命周期的增加，动脉血栓栓塞性疾病正在迅速成为儿科三级护理中心的新流行病。 然而，预防或治疗这种危及生命和肢体的疾病的治疗选择有限，例如 ECMO 以及用于修复复杂先天性心脏病的新手术技术和移植材料。由于了解新生儿、婴儿和儿童的血小板在受损血管中形成血栓的程度，(ii) 关于各种药物的能力的信息有限。 减少儿科血小板在生理相关条件下介导的粘附和活化，以及(iii)缺乏允许使用最少量的血液以高通量方式快速评估儿科血小板对激动剂和拮抗剂的反应的复杂技术。临床相关问题，小容量微流体装置和高通量筛选（HTS）将用于预测血小板对激动剂和拮抗剂的多种组合的反应，而新型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：是否可以开发复杂的技术，以高通量方式使用最少量的血液快速评估儿童血小板对激动剂和拮抗剂的反应。是否可以确定新的药物用于未来的开发或使用？是否存在与年龄相关的功能差异，从而妨碍在某些儿科患者中使用特定的抗血小板药物？是否可以开发小动物模型来更好地评估儿科血小板反应？达到抗血栓的作用体外试验能否预测体内药物疗效？最终，我们相信本提案中概述的工作将有助于更好地了解适用于高危儿科患者的抗血小板药物类别。也许有可能 确定未来临床试验的可行性和招募标准，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相关，即鼓励转化和合作研究，以增进我们对潜在机制的了解。不同发育阶段儿童的药物作用和反应。