Nitrite based neuroprotection after cardiac arrest

描述(由申请人提供)：Dezfulian博士是一名成人和儿科重症监护医生，他敏锐地意识到他所关心的心脏骤停幸存者的复苏后治疗的匮乏。这一职业发展奖补充了他的研究背景，提供了高级导师以及神经科学和氧化还原信号方面的实验室和教学培训。该研究计划基于初步观察，支持这样一种假设，即心脏骤停后亚硝酸盐介导的神经保护是通过基于一氧化氮(NO)和S-亚硝硫醇(S-NO)的信号转导，通过靶向Delta蛋白激酶C和线粒体来防止随后的神经元死亡。这一假说将根据三个目标进行检验：(1)确定最佳亚硝酸盐剂量和时机，并量化基于NO-和S-NO的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通过亚硝酸化和三角洲蛋白激酶C(-PKC)失活来实现，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和防止细胞凋亡。德兹富利安博士将负责一项职业发展计划，包括：1.实验研究、实验室指导、期刊俱乐部以及他的导师和同事的科学审查和发展。2.迈阿密大学研究生课程。3.内部研讨会和国家会议和专题讨论会。4.负责任地进行研究方面的培训。5.由两名高级博士和两名博士组成的科学咨询委员会的指导。6.赠款编写、赠款审查和制定旨在实现独立的过渡计划。Dezfulian博士的神经科学导师将主要来自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成就卓著的神经学家，他研究脑缺血后神经保护和线粒体功能障碍的机制。Dezfulian博士将由跨学科干细胞研究所(ISCI)主任约书亚·黑尔博士共同指导。黑尔博士由美国国立卫生研究院资助，研究心力衰竭中的氧化应激，在亚硝基-氧化还原信号方面有着长期的研究记录，并将就被认为是亚硝酸盐介导的神经保护基础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，因为他执行了这项申请的研究目标，并过渡到作为临床科学家的独立。

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.