Nitrite based neuroprotection after cardiac arrest

描述（由申请人提供）：Dezfulian医生是一名成人和儿科重症监护医生，他敏锐地意识到他所照顾的心脏骤停幸存者缺乏复苏后治疗。这个职业发展奖项补充了他在神经科学和氧化还原信号方面的高级指导和实验室教学培训的研究背景。该研究计划基于支持下述假设的初步观察，即心脏骤停后亚硝酸盐介导的神经保护作用是通过一氧化氮（NO）和s -亚硝基硫醇（S-NO）为基础的信号传导，通过靶向δ蛋白激酶C和线粒体来防止随后的神经元死亡。这一假设将沿着三个目标进行验证：(1)确定最佳亚硝酸盐剂量和时间，并量化NO和S-NO信号在神经保护中的相对贡献，(2)测试亚硝酸盐介导的神经保护是否源于δ蛋白激酶C （- pkc）的亚硝基化和失活，以及(3)测试亚硝酸盐介导的NO和S-NO的产生是否影响线粒体功能并防止细胞凋亡。德兹富连博士将进行以下职业发展规划：实验研究，实验室指导，期刊俱乐部和科学评审和发展的导师和同事。2. 迈阿密大学研究生课程。3. 校内讨论会、全国会议和专题讨论会。4. 培训负责任的研究行为。5. 由两名高级博士和两名博士组成的科学咨询委员会提供指导。6. 奖助金的撰写、奖助金的检讨及以独立为目标的过渡计划的发展。Dezfulian博士的神经科学指导将主要来自CVDRC主任Miguel Perez-Pinzon博士。Perez-Pinzon博士是美国国立卫生研究院资助的一位有成就的神经科学家，他研究脑缺血后神经保护和线粒体功能障碍的机制。Dezfulian博士将与跨学科干细胞研究所（ISCI）主任Joshua Hare博士共同指导。Hare博士是美国国立卫生研究院资助的研究心力衰竭中的氧化应激的人，他在亚硝基氧化还原信号方面有着长期的研究记录，并将为亚硝酸盐介导的神经保护的关键机制途径提供指导。这个指导团队将指导Dezfulian博士的职业发展，因为他执行了这个应用程序的研究目标，并过渡到独立的临床科学家。

DESCRIPTION (provided by applicant): Dr. Dezfulian is an adult and pediatric critical care physician acutely aware of the paucity of post-resuscitation therapies for the cardiac arrest survivors he cares for. This career development award supplements his research background with senior mentorship and lab-based and didactic training in neurosciences and redox signaling. The research plan is based on preliminary observations which support the hypothesis that nitrite-mediated neuroprotection after cardiac arrest occurs through nitric oxide (NO) and S-nitrosothiol (S-NO)-based signaling that prevents subsequent neuronal death by targeting delta protein kinase C and mitochondria. This hypothesis will be tested along three aims: (1) to define the optimal nitrite dose and timing and quantify the relative contributions of NO- and S-NO based signaling in neuroprotection, (2) to test whether nitrite-mediated neuroprotection results from nitrosylation and inactivation of delta protein kinase C (-PKC), and (3) to test whether nitrite-mediated NO and S-NO production affects mitochondrial function and prevents apoptosis. Dr. Dezfulian will undertake a career development plan consisting of: 1. Experimental research, laboratory instruction, journal clubs and scientific review and development by his mentors and colleagues. 2. Coursework through the University of Miami graduate program. 3. Intramural seminars and national conferences and symposia. 4. Training in the responsible conduct of research. 5. Guidance by a scientific advisory committee consisting of two senior MDs and two PhDs. 6. Grant writing, grant review and development of a transition plan aimed at independence. Dr. Dezfulian's neuroscience mentorship will primarily come from Dr. Miguel Perez-Pinzon, CVDRC director. Dr. Perez-Pinzon is an accomplished NIH-funded neuroscientist who studies mechanisms of neuroprotection and mitochondrial dysfunction after brain ischemia. Dr. Dezfulian will be co-mentored by Dr. Joshua Hare, Director of the Interdisciplinary Stem Cell Institute (ISCI). Dr. Hare is NIH-funded to investigate oxidative stress in heart failure, has a long track record of research in nitroso-redox signaling, and will provide guidance regarding key mechanistic pathways believed to underlie nitrite mediated neuroprotection. This mentorship team will guide Dr. Dezfulian's career development as he executes the research aims of this application and transitions to independence as a clinician scientist. PUBLIC HEALTH RELEVANCE: This career development awards provides Dr. Cameron Dezfulian, an intensive care unit physician, with salary and research support to pursue a career development plan aimed at making him an independent clinician scientist studying ways to reduce brain injury after cardiac arrest. Dr. Dezfulian will be mentored by two senior scientists at the University of Miami and conduct research aimed at discovering new ways to signal protection in brain after cardiac arrest to prevent the brain injury that normally results.