Using Microfluidics to Identify Mechanisms of Platelet Dysfunction and Assess Therapeutic Efficacy in Traumatic Hemorrhage

使用微流控技术识别血小板功能障碍的机制并评估外伤性出血的治疗效果

• 批准号: 10351512
• 负责人: Susan Marguerite Shea
• 金额: $ 12.91万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-05 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10351512
• 关键词: Address; Admission activity; Age-Years; Agonist; Biological; Biological Assay; Biomedical Engineering; Bleeding time procedure; Blood Platelets; Blood Vessels; Blood specimen; Caring; Cause of Death; Cessation of life; Clinical; Clinical Trials; Clot retraction; Coagulation Process; Data; Development; Doctor of Philosophy; End Point Assay; Ensure; Etiology; Five-Year Plans; Functional disorder; Funding; Goals; Hemorrhage; Hemostatic Agents; Hemostatic function; Hospitalization; Hour; In Vitro; Individual; Injury; Institution; Interdisciplinary Study; Kinetics; Knowledge; Lead; Licensing; Measures; Mediator of activation protein; Mentors; Mentorship; Metabolic; Microfluidics; Microscopy; Mission; Modeling; Molecular; Morphology; National Heart, Lung, and Blood Institute; Outcome; Patients; Phenotype; Physiological; Plasma; Platelet Transfusion; Porosity; Productivity; Recording of previous events; Research; Research Personnel; Resources; Resuscitation; Risk; SELP gene; Sampling; Signal Transduction; Structure; Surface; Technical Expertise; Temperature; Testing; Therapeutic; Time; Transfusion; Translational Research; Trauma; Trauma patient; Traumatic Hemorrhage; Traumatic injury; Treatment Efficacy; United States; United States National Institutes of Health; Universities; Venous; Washington; Work; aged; blood product; clinical development; clinical efficacy; experience; innovation; insight; medical schools; mortality; mortality risk; novel; platelet function; platelet phenotype; point of care; pre-clinical assessment; preclinical study; prevent; preventable death; programs; ratiometric; receptor; success; synergism; therapy development; tool; transfusion medicine; translational scientist; trauma induced coagulopathy

Using Microfluidics to Identify Mechanisms of Platelet Dysfunction and Assess Therapeutic Efficacy in Traumatic Hemorrhage Project Summary/Abstract This proposal consists of a five-year plan to develop Susan M. Shea, PhD into an independent translational scientist in the field of trauma-induced coagulopathy (TIC) and therapeutic assessment of hemostatic blood products. Washington University School of Medicine (WUSM) is an outstanding institution for Dr. Shea to establish her research program, as there is a longstanding history of NIH-funded research, as well as both breadth and depth of resources available. Additionally, there is a high level of synergy and multidisciplinary collaboration among departments, and with other institutions, both of which are manifested in Dr. Shea’s proposed mentoring team and advisory panel. A structured educational program is proposed to provide Dr. Shea with additional knowledge, technical skills, grantsmanship, networking, and mentorship required to achieve a successful transition to independence. Dr. Shea’s immediate goal is to fulfill the aims outlined in this proposal. Trauma is the most common cause of death in the United States in individuals less than 46 years of age, to include 30,000 deaths from hemorrhage per year that could be prevented with more timely and appropriate care. TIC occurs in 25% of trauma patients and is associated with a 4 fold risk of mortality. Platelet dysfunction is one of the main etiologies of TIC, and is a poorly understood phenomenon. TIC-related platelet dysfunction is challenging to study as current clinical assays are not physiologically relevant to hemostatic function. Furthermore, the optimal therapeutic approach to address TIC-related platelet dysfunction is unknown. The aims of Dr. Shea’s research in this proposal include the following: 1. Characterize trauma-induced coagulopathy (TIC)-related platelet dysfunction in the context of global hemostasis and its association with mortality. 2. Define the relative contributions of cellular and soluble mediators to TIC-related platelet dysfunction. 3. Determine which transfusion strategies are effective at reversing platelet dysfunction in TIC. The knowledge gained from the successful effectuation of these aims will result in novel insight into mechanisms of trauma-induced platelet dysfunction and therapeutic efficacy. This will be the first time resuscitation of TIC will be investigated in a microfluidic model of bleeding. Such a platform has the potential to be used for licensing of hemostatic blood products, adjuncts, and agents, as well as to provide the biologic rationale for the development of clinical trials that can assess the clinical efficacy of hemostatic products. This proposal is directly relevant to National Heart, Lung, and Blood Institute (NHLBI) mission, as the long-term objective is to use a biofidelic model of hemostasis to define the mechanisms of and develop therapies for TIC-related platelet dysfunction.

使用微流控技术识别血小板功能障碍的机制并评估治疗效果 外伤出血 项目概要/摘要 该提案包括一项五年计划，旨在将 Susan M. Shea 博士发展成为独立的翻译家 创伤性凝血病 (TIC) 和止血治疗评估领域的科学家 华盛顿大学医学院 (WUSM) 是 Shea 博士的杰出机构。 建立她的研究计划，因为 NIH 资助的研究有着悠久的历史，而且 此外，可用资源的广度和深度也具有高水平的协同作用和多学科性。 部门之间以及与其他机构之间的合作，这两者都体现在 Shea 博士的 建议为 Shea 博士提供一个结构化的教育计划。 拥有实现目标所需的额外知识、技术技能、资助、网络和指导 成功过渡到独立。 谢伊博士的近期目标是实现该提案中概述的目标。创伤是最常见的原因。 美国 46 岁以下个体死亡人数，其中 30,000 人死于出血 每年有 25% 的创伤患者发生 TIC，通过更及时和适当的护理是可以预防的。 血小板功能障碍是 TIC 的主要病因之一，与 4 倍的死亡风险相关。 目前对 TIC 相关血小板功能障碍的了解尚不清楚。 此外，测定与止血功能没有生理相关性。 解决 TIC 相关的血小板功能障碍尚不清楚。Shea 博士在该提案中的研究目的包括： 下列： 1. 描述创伤性凝血病 (TIC) 相关血小板功能障碍的背景 整体止血及其与死亡率的关系。 2. 定义细胞和可溶性介质对 TIC 相关血小板的相对贡献 功能障碍。 3. 确定哪些输血策略可有效逆转 TIC 中的血小板功能障碍。 从成功实现这些目标中获得的知识将带来对机制的新见解 创伤引起的血小板功能障碍和治疗效果的研究这将是第一次 TIC 复苏。 在出血的微流体模型中进行研究，这样的平台有可能用于许可。 止血血液制品、辅助剂和制剂，并为开发提供生物学原理 该提案与可评估止血产品临床疗效的临床试验直接相关。 国家心肺血液研究所 (NHLBI) 的使命，因为长期目标是使用生物忠实模型 止血以确定 TIC 相关血小板功能障碍的机制并开发治疗方法。