Genetics and Brain Ischemia in the Critically Ill

描述(由申请人提供)：这份K24职业中期调查员申请书描述了调查员对以患者为导向的研究的奉献精神，她指导年轻研究人员的经验，以及该奖项将如何巩固和发展这些职业承诺。这一应用的临床重点是确定遗传因素，以最大限度地提高脑损伤危重患者的脑血流灌注。本研究的具体目的是：1)描述在脑损伤后急性期脑脊液中发现的两种常见线粒体DNA(MtDNA)缺失(4799bp和7436bp)的发生率；2)确定mtDNA缺失的存在是否与脑供血和代谢有关，以及3)确定mtDNA缺失是否与预后相关[格拉斯哥预后评分(GOS)和死亡率]。将使用描述性比较设计来确定mtDNA缺失的存在是否会降低脑血流量(CBF)和新陈代谢，并导致重症脑损伤患者的预后较差。目前资助的两个临床研究项目[预测蛛网膜下腔出血迟发性脑缺血的方法，以及载脂蛋白E基因型对创伤性脑损伤成人预后的影响]将为指导活动提供基础，这些活动将增强和发展年轻研究人员的临床研究技能。它们还将提供患者数据，包括侮辱的时间、严重程度、类型和位置、人口统计信息、用于分析的脑脊液、脑血流量和缺血数据、生理参数和结果评估。长期的职业目标是根据遗传变异确定患者的特征，这将使临床医生能够设计个性化的干预措施，以最大限度地增加脑血流。严重脑损伤患者个体间差异的重点将提供在设计、实施、评估和传播临床研究方面教育和指导初级临床研究人员的机会，这些研究将从长期来看改善患者的结果。这些研究被设计为基础科学和临床科学的结合，以便将结果直接应用于临床实践。为了最大限度地提高脑血流灌注，纳入了个人的S基因档案，为培训下一代以患者为导向的重症监护研究人员提供了一个极好的平台。

DESCRIPTION (provided by applicant): This K24 Midcareer Investigator application describes the investigator's dedication to patient-oriented research, her experience in mentoring young researchers, and how this award would consolidate and develop these career commitments. The clinical focus of this application is the identification of genetic factors that will maximize cerebral perfusion in the critically ill patient with brain injury. The specific aims for this study are to: 1) describe the incidence of two common mitochondrial DNA (mtDNA) deletions (4799bp and 7436 bp) found in the cerebrospinal fluid (CSF) within the acute phase following brain injury; 2) determine whether the presence of mtDNA deletions are associated with cerebral profusion and metabolism and; 3) determine whether mtDNA deletions are associated with outcomes [Glasgow Outcomes Scale (GOS) and morality]. A descriptive comparative design will be used to determine whether the presence of mtDNA deletions decreases cerebral blood flow (CBF) and metabolism and results in poorer outcomes in critically ill brain injured patients. Two currently funded clinical research projects [Methods of Predicting Delayed Cerebral lschemia in Subarahnoid Hemorrhage, and The Effect of ApoE Genotype on Outcomes in Traumatic Brain Injured Adults] will provide the foundation for the mentoring activities that will enhance and develop young investigators' clinical research skills. They will also provide patient data on the timing, severity, type, and location of insult, demographic information, CSF for analysis, CBF and ischemia data, physiologic parameters and outcome evaluation. The long-term career objective is to identify profiles of patients based on genetic variation that will allow clinicians to design individualized interventions to maximize cerebral perfusion. The focus of inter-individual variations of patients with a severe brain injury will provide the opportunity to educate and mentor junior clinical investigators in the design, implementation, evaluation and dissemination of clinical studies that will, in the long term, improve patient outcomes. The studies are designed as a combination of basic and clinical science in order to directly apply the results to clinical practice. The incorporation of an individual' s genetic profile for maximizing cerebral perfusion provides an excellent platform for training the next generation of patient-oriented critical care researchers.