An Integrated Investigation of the Interaction Between PUFAs and Genetic Variants in Trauma and Critical Care

项目摘要 Elaheh Rahbar博士要求在博士的指导下进行为期5年的教学量化培训。 卡尔·朗费尔德、弗洛伊德·切尔顿、查尔斯·麦考尔和D.克拉克·菲尔斯。早期职业生涯的主要原因 过渡奖包括：i)Pi被聘为创伤研究领域的助理教授，ii)Pi没有 曾接受过统计基因组学或脂类代谢方面的正式培训，以及iii)PI内在的了解 并使用数学方法改进创伤和损伤后炎症性疾病的治疗 建模技术。在这个K25量化指导的职业发展项目中，PI建议 开发包含混合和多层次交互的复杂数学和统计模型 在饮食和内源脂肪酸与遗传、表观遗传和其他生理标志之间更好地 了解如何减弱对创伤的急性反应。我们已经编制了一个强有力的组合 包括教学培训、正式课程作业和指导，以开发和验证多因素数学 创伤性损伤模型。这包括统计基因组学方面的培训，以及在 分别由朗费尔德博士和切尔顿博士指导。维克森林提供了出色的环境 追求这个研究和职业发展奖，因为它鼓舞人心的跨学科氛围。 具体地说，我们将首先评估脂肪酸代谢的作用和遗传/表观遗传的贡献 脂肪酸脱饱和酶(FADS)基因变异对炎症和凝血功能的影响 危重病人。利用之前收集的生物标本和NIH资助的临床数据集(例如 欧米茄试验；Glue Grant)我们还将开发新的集成基因组模型来评估饮食的影响 多不饱和脂肪酸(PUFA)干预治疗创伤。我们假设具体的 FADS基因簇(11号染色体；12-13q)中的变异在调节血脂和 对损伤的炎症反应，因此可能是不同发现的原因。 此外，这些遗传/表观遗传因素可能是调节饮食反应的关键因素。 对危重病人进行多不饱和脂肪酸干预，如ω-3多不饱和脂肪酸。新的多水平统计基因组模型 在此期间开发的K25将深入了解遗传/表观遗传变异在 FADS基因簇在炎症、血栓形成和代谢反应中的相互作用 一次受伤。拟议的研究具有重要意义，因为普遍缺乏适当的定量 方法评估创伤的动态反应和对遗传因素作用的低估 调节对伤害的生理反应。这种方法是创新的，因为它试图利用 数学和统计基因组技术，以提高我们对创伤的病理生理学的知识。 总之，拟议的培训和研究计划将开启拉赫巴尔博士作为独立R01- 在急性创伤和重症护理的精准医学和营养基因组学领域获得资助的研究人员和领导者。

Project Summary Elaheh Rahbar, PhD is requesting 5 years of didactic quantitative training under the supervision of Drs. Carl Langefeld, Floyd Chilton, Charles McCall and D. Clark Files. Primary reasons for this early career transition award include: i) PI was hired as an Assistant Professor in the area of trauma research, ii) PI has not been formally trained in statistical genomics or lipid metabolism, and iii) the PI's inherent desire to understand and improve treatments for traumatic injuries and inflammatory morbidities following injury using mathematical modeling techniques. In this K25 quantitative mentored career development project, the PI proposes to develop sophisticated mathematical and statistical models that incorporate mixed and multi-level interactions between dietary and endogenous fatty acids and genetic, epigenetic and other physiologic markers to better understand how to attenuate the acute response to traumatic injuries. We have compiled a strong combination of didactic training, formal coursework, and mentorship to develop and validate a multi-factorial mathematical model of traumatic injuries. This includes training in statistical genomics, and lipid metabolism under the guidance of Drs. Langefeld and Chilton, respectively. Wake Forest provides an outstanding environment to pursue this research and career development award because of its encouraging interdisciplinary atmosphere. Specifically, we will first evaluate the role of fatty acid metabolism and contribution of genetic/epigenetic variations within the fatty acid desaturase (FADS) gene cluster on changes in inflammation and coagulation in critically ill patients. Leveraging on previously collected bio-specimens and NIH funded clinical datasets (e.g. OMEGA trial; Glue Grant) we will also develop new integrated genomic models to assess the effect of dietary polyunsaturated fatty acid (PUFA) interventions for the treatment of trauma. We hypothesize that specific variants within the FADS gene cluster (chromosome 11; 12-13q) play a critical role in regulating lipid and inflammatory responses to injuries and consequently are potentially responsible for the disparate findings. Furthermore, these genetic/epigenetic factors are possibly key players in regulating the response to dietary PUFA interventions, such as ω-3 PUFAs, in the critically ill. The novel multi-level statistical genomic models developed during this K25 will provide insight into the contribution of genetic/epigenetic variants within the FADS gene cluster on the interactive nature of inflammatory, thrombogenic and metabolic responses following an injury. The proposed research is significant because there is a general lack of appropriate quantitative methods to evaluate the dynamic responses to trauma and an under-appreciation for the role of genetic factors modulating the physiologic responses to injury. The approach is innovative, because it attempts to use mathematical and statistical genomic techniques to advance our knowledge of the pathophysiology of trauma. In summary, the proposed training and research plan will launch Dr. Rahbar's career as an independent R01- funded researcher and leader in precision medicine and nutri-genomics for acute trauma and critical care.