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

项目总结

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.