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

项目摘要 Elahe Rahbar博士要求在Dr. Carl Langefeld、弗洛伊德Chilton、Charles McCall和D.克拉克档案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 在统计基因组学或脂质代谢方面接受过正式培训，以及iii）PI固有的了解 并利用数学方法改善创伤性损伤和损伤后炎症的治疗 建模技术在这个K25定量指导职业发展项目中，PI建议 开发复杂的数学和统计模型，包括混合和多层次的相互作用 膳食和内源性脂肪酸与遗传、表观遗传和其他生理标记之间的关系， 了解如何减轻创伤后的急性反应。我们已经编制了一个强大的组合 教学培训，正式课程和指导，以开发和验证多因素数学 创伤模型。这包括在统计基因组学的培训，以及根据 分别由朗格菲尔德和奇尔顿博士指导维克森林提供了一个出色的环境， 追求这个研究和职业发展奖，因为它鼓励跨学科的气氛。 具体来说，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。 脂肪酸去饱和酶（FADS）基因簇内的变异对炎症和凝血的影响， 危重病人。利用先前收集的生物样本和NIH资助的临床数据集（例如， OMEGA试验; Glue Grant），我们还将开发新的整合基因组模型，以评估膳食营养素的影响。 多不饱和脂肪酸（PUFA）干预治疗创伤。我们假设 FADS基因簇（染色体11; 12- 13 q）内的变体在调节脂质和 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。 PUFA干预，如ω-3 PUFA，在危重病中。新型多层次统计基因组模型 在K25期间开发的新技术将深入了解遗传/表观遗传变异在 FADS基因簇对以下炎症，血栓形成和代谢反应的相互作用性质的影响 一个伤口建议的研究是有意义的，因为普遍缺乏适当的定量 评估对创伤的动态反应的方法以及对遗传因素作用的低估 调节对损伤的生理反应。这种方法是创新的，因为它试图使用 数学和统计基因组技术，以促进我们的创伤病理生理学的知识。 总之，拟议的培训和研究计划将启动Rahbar博士作为独立R 01的职业生涯- 在急性创伤和重症监护的精确医学和营养基因组学方面，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.