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

多不饱和脂肪酸与基因变异在创伤和重症监护中相互作用的综合研究

• 批准号: 10348226
• 负责人: Elaheh Rahbar
• 金额: $ 5.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348226
• 关键词: 13q; Acute; Adjuvant; Adult Respiratory Distress Syndrome; Affect; Age; Alleles; Area; Attenuated; Biological; Biological Markers; Career Transition Award; Chromosome 11; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Complex; Confounding Factors (Epidemiology); Critical Care; Critical Illness; Data; Data Set; Diet; Dietary Intervention; Doctor of Philosophy; Enrollment; Enteral; Environment; Epigenetic Process; Fatty Acid Desaturases; Fatty Acids; Functional disorder; Funding; Futility; Future; Gene Cluster; Generations; Genes; Genetic; Genetic Variation; Genomics; Genotype; Glues; Goals; Grant; Immune response; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intervention; Investigation; K-Series Research Career Programs; Knowledge; Lipid Biochemistry; Lipids; Mathematics; Mediating; Mentors; Mentorship; Metabolic; Methods; Minor; Modeling; Morbidity - disease rate; Multiple Organ Failure; N-3 polyunsaturated fatty acid; National Institute of General Medical Sciences; Nature; Omega-3 Fatty Acids; Patient Care; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Physiological; Play; Polyunsaturated Fatty Acids; Population; Randomized Clinical Trials; Regulation; Research; Research Personnel; Role; Sepsis; Specimen; Statistical Models; Supercomputing; Supervision; Techniques; Testing; Training; Trauma; Trauma Research; Trauma patient; Traumatic injury; United States National Institutes of Health; Variant; career; career development; cohort; collaborative environment; data repository; design; dietary; dietary supplements; epigenetic variation; fatty acid metabolism; fatty acid supplementation; forest; genetic variant; genomic variation; improved; innovation; insight; lipid metabolism; mathematical model; metabolomics; mortality; novel; nutrition; nutritional genomics; precision medicine; professor; research and development; response; response to injury; severe injury; success; systemic inflammatory response; thrombogenesis; trauma care

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.

项目摘要 在DRS的监督下，Elaheh Rahbar博士要求进行5年的教学定量培训。 Carl Langefeld，Floyd Chilton，Charles McCall和D. Clark文件。早期职业的主要原因 过渡奖包括：i）PI被聘为创伤研究领域的助理教授，ii）PI尚未 我们接受了统计基因组学或脂质代谢的正式培训，iii）PI继承了理解的愿望 并改善使用数学损伤后的创伤性损伤和炎症性炎症的治疗方法 建模技术。在这个K25定量修复职业发展项目中，PI提出的建议 开发复杂的数学和统计模型，这些模型结合了混合和多层相互作用 在饮食和内源性脂肪酸以及遗传，表观遗传和其他生理标记之间 了解如何减轻对创伤性损伤的急性反应。我们已经编译了一个强大的组合 教学培训，正式课程和心态，以发展和验证多因素数学 创伤性损伤模型。这包括统计基因组学的培训和脂质代谢 Drs的指导。兰格菲尔德和奇尔顿分别。韦克森林为 由于其令人鼓舞的跨学科氛围，因此获得了这一研究和职业发展奖。 具体而言，我们将首先评估脂肪酸代谢的作用和遗传/表观遗传学的贡献 脂肪酸去饱和酶（FADS）基因簇内的变化在炎症和凝结变化上 重病患者。利用先前收集的生物特异性和NIH基本临床数据集（例如， 欧米茄审判；胶水赠款）我们还将开发新的综合基因组模型来评估饮食的影响 多不饱和脂肪酸（PUFA）治疗创伤的干预措施。我们假设该具体 FADS基因簇（染色体11; 12-13Q）中的变体在调节脂质和 炎症对伤害的反应，因此可能导致不同的发现。 此外，这些遗传/表观遗传因素可能是控制对饮食反应的关键参与者 PUFA干预措施，例如ω-3 PUFA，重病。新型的多级统计基因组模型 在此K25期间开发的将洞悉遗传/表观遗传变异的贡献 FADS基因簇在炎症，血栓形成和代谢反应的互动性质上 受伤。拟议的研究很重要，因为普遍缺乏适当的定量 评估对创伤的动态反应的方法和遗传因素作用的低调 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，以促进我们对创伤病理生理学的了解。 总而言之，拟议的培训和研究计划将启动Rahbar博士作为独立R01-的职业生涯 急性创伤和重症监护的精密医学和营养基因组学的研究人员和领导者。

项目成果

Uncovering the DNA methylation landscape in key regulatory regions within the FADS cluster.

• DOI: 10.1371/journal.pone.0180903
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Rahbar E;Ainsworth HC;Howard TD;Hawkins GA;Ruczinski I;Mathias R;Seeds MC;Sergeant S;Hixson JE;Herrington DM;Langefeld CD;Chilton FH
• 通讯作者: Chilton FH

Acquired antithrombin deficiency is a risk factor for venous thromboembolism after major trauma.

• DOI: 10.1016/j.thromres.2021.05.015
• 发表时间: 2021-08
• 期刊: THROMBOSIS RESEARCH
• 影响因子: 7.5
• 作者: Rahbar, Elaheh;Cotton, Bryan A.;Wade, Charles E.;Cardenas, Jessica C.
• 通讯作者: Cardenas, Jessica C.

Allele-specific methylation in the FADS genomic region in DNA from human saliva, CD4+ cells, and total leukocytes.

• DOI: 10.1186/s13148-018-0480-5
• 发表时间: 2018
• 期刊: Clinical epigenetics
• 影响因子: 5.7
• 作者: Rahbar E;Waits CMK;Kirby EH Jr;Miller LR;Ainsworth HC;Cui T;Sergeant S;Howard TD;Langefeld CD;Chilton FH
• 通讯作者: Chilton FH

Impact of rs174537 on Critically Ill Patients with Acute Lung Injury: A Secondary Analysis of the OMEGA Randomized Clinical Trial.

• DOI: 10.1093/cdn/nzaa147
• 发表时间: 2020-10
• 期刊: Current developments in nutrition
• 影响因子: 4.8
• 作者: Dosso B;Waits CMK;Simms KN;Sergeant S;Files DC;Howard TD;Langefeld CD;Chilton FH;Rahbar E
• 通讯作者: Rahbar E