Platelet activation in septic shock

描述（由申请人提供）：Michael Puskarich，医学博士，密西西比大学医学中心急诊医学系助理教授，将利用K-23奖转型为独立的以患者为导向的研究人员。Puskarich博士在同行评议期刊上发表了18篇论文，在获得K-23奖之前，他将完成德雷克塞尔大学临床研究硕士学位课程。他的职业目标是成为一名在转化急诊医学研究方面拥有全国公认专业知识的领先临床医生。为候选人Michael Puskarich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。他的指导团队包括一位主要导师，医学博士艾伦·e·琼斯；共同导师乔治·戴尔博士；以及由Jonathan Holser博士、Jeffrey Kline医学博士、Merry Lindsey博士和Richard Summers医学博士组成的顾问委员会。他们拥有广泛的专业知识和经验，可以为候选人提供专业发展所需的工具。与他的导师一起，Puskarich博士为他成功的职业发展确定了几个目标。这些包括(1)提高他在临床和转化败血症研究方面的专业知识和经验；(2)提高翻译研究水平；(3)提高他在血小板、微循环和线粒体生理学方面的知识；(4)获得额外的科学和基金写作经验；（五）提高学术带头人地位；(6)成为他人的有效导师。Puskarich博士将通过严格的职业发展计划来实现这些目标，包括正式课程，专业培训，参加研讨会和研讨会，积极参与专业协会和大学范围内的委员会，定期与他的导师和他的学员咨询委员会成员会面，并完成他的研究学习。已经确定了Puskarich博士的每个职业发展活动的里程碑和估计的专业时间分配。普斯卡里奇博士提议的研究项目是一项辅助研究

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.