Platelet activation in septic shock

感染性休克中的血小板活化

• 批准号: 8804343
• 负责人: Michael A. Puskarich
• 金额: $ 18.98万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-12 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804343
• 关键词: Advisory Committees; Affect; Agonist; Ancillary Study; Area; Award; Blood Coagulation Factor; Blood Platelets; Blood flow; Carnitine; Cause of Death; Cell Respiration; Clinical; Clinical Research; Clinical Trials; Collagen; Complex; Development; Development Plans; Diagnosis; Disease; Doctor of Philosophy; Dose; Double-Blind Method; Educational workshop; Emergency Medicine; Enrollment; Environment; Flow Cytometry; Funding; Generations; Goals; Grant; Health; Hospitals; Hour; In Vitro; Incidence; Inflammatory; Infusion procedures; Injury; Intervention; Investigation; Journals; Knowledge; Lead; Letters; Levocarnitine; Master' s Degree; Measurement; Measures; Medical center; Mentors; Mississippi; Mitochondria; National Institute of General Medical Sciences; Nature; Oligomycins; Organ failure; Outcome; Parents; Pathogenesis; Pathway interactions; Patients; Peer Review; Physiology; Placebo Control; Placebos; Platelet Activation; Play; Probability; Publications; Randomized; Reactive Oxygen Species; Research; Research Design; Research Infrastructure; Research Personnel; Research Project Grants; Research Technics; Resolution; Respiration; Role; Schedule; Scientist; Secondary to; Sepsis; Septic Shock; Side; Societies; Stream; Testing; Therapeutic; Thrombin; Thrombosis; Time; Training; Translational Research; United States National Institutes of Health; Universities; Vasoconstrictor Agents; Video Microscopy; Work; Writing; career; career development; convulxin; design; experience; human subject protection; improved; in vivo; indexing; meetings; member; mimetics; mitochondrial membrane; mortality; novel; novel strategies; patient oriented; professor; programs; public health relevance; research study; response; tool

DESCRIPTION (provided by applicant): Michael Puskarich, MD, an Assistant Professor in the University of Mississippi Medical Center's Department of Emergency Medicine, will utilize this K-23 Award to transition into an independent patient-oriented researcher. Author of 18 publications in peer-reviewed journals, Dr. Puskarich will have completed Drexel University's Master's degree program in Clinical Research prior to receipt of his K-23 Award. His career goal is to be a leading clinician scientist with nationally recognized expertise in translational emergency medicine research. The Mentoring Plan developed for the candidate, Michael Puskarich, MD, is comprehensive in nature and designed to accommodate Dr. Puskarich's transition to an independent research investigator during this award's project period. His mentoring team includes a Primary Mentor, Alan E. Jones, MD; a Co-Mentor, George Dale, PhD; and a Mentee Advisory Committee, consisting of Jonathan Holser, PhD, Jeffrey Kline, MD, Merry Lindsey, PhD, and Richard Summers, MD. Together, they have the breadth of expertise and experience to provide the candidate with the tools he needs for his professional development. Together with his mentors, Dr. Puskarich has identified several objectives for his successful career development. These include (1) advancing his expertise and experience in clinical and translational sepsis research; (2) enhancing his translational research techniques; (3) advancing his knowledge of platelet, microcirculatory, and mitochondrial physiology; (4) gaining additional experience in scientific and grant writing; (5) enhancing his standing as an academic leader; and (6) becoming an effective mentor to others. Dr. Puskarich will accomplish these objectives through a rigorous career development plan that includes formal coursework, specialized training, attendance at workshops and seminars, active participation in professional societies and on university-wide committees, regular scheduled meetings with his mentors and members of his Mentee Advisory Committee, and completion of his research study. Milestones and estimated allocation of Dr. Puskarich's professional time for each of his career development activities have been identified. Dr. Puskarich's proposed research project is an ancillary study of an ongoing NIGMS-funded project (R01GM103799-01), for which Dr. Puskarich's primary mentor serves as PI. The ancillary study has been approved by the parent study's DSMB, and a letter of support is included in the Protection of Human Subjects section. The primary aim of the parent study, L-Carnitine Treatment for Vasopressor Dependent Septic Shock" (more commonly referred to as the Rapid Administration of Carnitine in sEpsis-or RACE Study) is to assess whether L-carnitine reduces cumulative organ failure and predicted probability of mortality in patients with septic shock. The study design is that of a randomized, double-blind, placebo-controlled, dose/efficacy-finding trial that utilizes a Bayesian adaptive approach and response-adaptive randomization. Within 24 hours of the diagnosis of septic shock, patients are randomized to a 12 hour infusion of one of three doses of L-carnitine (6, 12, or 18 grams) or placebo and followed to outcome. Up to 250 patients from 10 hospitals throughout the U.S. will be participating, and the study is currently in its first year of patient enrollment. Dr. Puskarichwill be able to take advantage of the infrastructure of the parent study and explore areas of inquiry not included in the parent study; specifically, the role of highly activated (HA) platelets in sepss; the significance of altered platelet mitochondrial function in the pathogenesis of sepsis; and the effects of L- carnitine on cellular respiration and HA platelet formation. The study is designed to achieve three specific aims: Aim #1: Determine if the percentage of HA platelets generated following DA stimulation in vitro is increased in patients with sepsis compared to matched controls, and determine if this percentage is associated with microcirculatory flow index (MFI) and Sequential Organ Failure Assessment (SOFA) score. The hypothesis is that sepsis increases the propensity for platelets to become highly activated following dual-agonist (DA) stimulation with thrombin and convulxin (a collagen mimetic) in vitro. This in vitro measurement reflects the in vivo environment in sepsis, which is characterized by high circulating thrombin and endothelial damage, with exposure of subendothelial collagen. As HA platelets are highly procoagulant, an increase in their formation will promote microcirculatory thrombosis and organ failure. Aim #2: : Determine if the percentage of HA platelets generated following SA stimulation in vitro is increased in patients with sepsis compared to matched controls, is associated with leak respiration, and is associated with MFI and SOFA score. The hypothesis is that a subset of platelets is primed for a HA transition following SA-stimulation with thrombin alone secondary to sepsis-induced reactive oxygen species (ROS) injury, evidenced by increased leak respiration. This subset of platelets, in turn, further contributes to microcirculatory thrombosis and organ failure. Aim #3: Test if L-carnitine treatment significantly decreases leak respiration and SA-stimulated HA platelet formation compared to placebo, with concomitant improvements in MFI and SOFA score. The hypothesis is that L-carnitine treatment will decrease SA-stimulated, but not DA-stimulated HA platelet formation, with concomitant decreases in thrombosis and organ failure. L-carnitine decreases sepsis-induced ROS damage, decreasing formation of SA-stimulated HA platelets. This decrease, in turns, mitigates microcirculatory thrombosis and organ failure.

描述（由申请人提供）：密西西比大学医学中心急诊医学系助理教授 Michael Puskarich 医学博士将利用该 K-23 奖项转型为以患者为导向的独立研究人员。 Puskarich 博士在同行评审期刊上发表了 18 篇论文，在获得 K-23 奖之前，他将完成德雷克塞尔大学的临床研究硕士学位课程。他的职业目标是成为一名领先的临床科学家，在转化急诊医学研究方面拥有全国公认的专业知识。为候选人 Michael Puskarich 医学博士制定的指导计划本质上是全面的，旨在适应 Puskarich 博士在该奖项项目期间向独立研究调查员的过渡。他的指导团队包括首席导师 Alan E. Jones（医学博士）；共同导师乔治·戴尔博士；学员咨询委员会由 Jonathan Holser 博士、Jeffrey Kline 医学博士、Merry Lindsey 博士和 Richard Summers 医学博士组成。他们拥有广泛的专业知识和经验，可以为候选人提供职业发展所需的工具。普斯卡里奇博士与他的导师一起确定了他成功职业发展的几个目标。这些包括（1）提升他在临床和转化脓毒症研究方面的专业知识和经验； （2）提高转化研究技术； (3) 增进血小板、微循环和线粒体生理学方面的知识； (4) 获得科学和资助写作方面的额外经验； （五）提高学术带头人的地位； (6) 成为他人有效的导师。 Puskarich 博士将通过严格的职业发展计划来实现这些目标，其中包括正式课程、专业培训、参加讲习班和研讨会、积极参与专业协会和大学范围内的委员会、定期与他的导师和受训者举行会议顾问委员会，并完成他的研究。已经确定了 Puskarich 博士每项职业发展活动的里程碑和估计的专业时间分配。 Puskarich 博士提出的研究项目是一项辅助研究 一个正在进行的 NIGMS 资助的项目 (R01GM103799-01)，Puskarich 博士的主要导师担任该项目的 PI。辅助研究已获得母研究 DSMB 的批准，并且支持信包含在“人类受试者保护”部分中。母研究“左旋肉碱治疗血管加压药依赖性败血性休克”（更常称为脓毒症中肉碱快速给药或 RACE 研究）的主要目的是评估左旋肉碱是否能减少累积性器官衰竭和预测概率该研究设计是一项随机、双盲、安慰剂对照、剂量/疗效探索试验，采用贝叶斯自适应方法和诊断感染性休克后 24 小时内，患者被随机分配接受三种剂量的左旋肉碱（6、12 或 18 克）或安慰剂中的一种 12 小时输注，并跟踪结果。来自美国 10 家医院的 250 名患者将参与其中，该研究目前正处于患者入组的第一年，Puskarich 博士将能够利用该研究的基础设施。母体研究并探索母体研究中未包含的探究领域；具体而言，高活化 (HA) 血小板在脓毒症中的作用；血小板线粒体功能改变在脓毒症发病机制中的重要性；以及左旋肉碱对细胞呼吸和 HA 血小板形成的影响。该研究旨在 实现三个具体目标：目标#1：确定脓毒症患者与匹配对照相比，体外 DA 刺激后生成的 HA 血小板百分比是否有所增加，并确定该百分比是否与微循环流量指数 (MFI) 和序贯器官相关失败评估 (SOFA) 分数。假设败血症会增加体外凝血酶和惊厥素（一种胶原模拟物）双重激动剂（DA）刺激后血小板高度活化的倾向。这种体外测量反映了脓毒症的体内环境，其特征是高循环凝血酶和内皮损伤，以及内皮下胶原蛋白暴露。由于HA血小板具有高度促凝血作用，其形成的增加将促进微循环血栓形成和器官衰竭。目标 #2：确定脓毒症患者与匹配对照相比，SA 体外刺激后生成的 HA 血小板百分比是否增加，是否与漏气呼吸相关，是否与 MFI 和 SOFA 评分相关。假设是，脓毒症引起的活性氧 (ROS) 损伤继发于单独使用凝血酶的 SA 刺激后，一部分血小板已准备好进行 HA 转变，这可以通过漏气呼吸增加来证明。反过来，这部分血小板又进一步导致微循环血栓形成和器官衰竭。目标#3：测试与安慰剂相比，左旋肉碱治疗是否显着降低漏气呼吸和 SA 刺激的 HA 血小板形成，并同时改善 MFI 和 SOFA 评分。假设左旋肉碱治疗会减少 SA 刺激的 HA 血小板形成，但不会减少 DA 刺激的 HA 血小板形成，同时减少血栓形成和器官衰竭。左旋肉碱可减少脓毒症引起的 ROS 损伤，减少 SA 刺激的 HA 血小板的形成。这种减少反过来又减轻了微循环血栓形成和器官衰竭。