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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 Elaheh Rahbar 博士要求在 Dr. Elaheh Rahbar 博士的监督下进行 5 年的定量教学培训。 Carl Langefeld、Floyd Chilton、Charles McCall 和 D. Clark Files 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 尚未接受过统计基因组学或脂质代谢方面的正式培训，并且 iii) PI 固有的理解愿望并利用数学方法改善创伤性损伤和损伤后炎症性疾病的治疗在这个 K25 定量指导的职业发展项目中，PI 建议：开发复杂的数学和统计模型，其中包含混合和多层次的交互饮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，以更好地了解如何减轻对创伤性伤害的急性反应我们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这包括统计基因组学和脂质代谢方面的培训。 Langefeld 博士和 Chilton 博士分别提供了良好的环境。因其令人鼓舞的跨学科氛围而获得这一研究和职业发展奖。具体来说，我们将首先评估脂肪酸代谢的作用以及遗传/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变化的影响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来评估饮食的影响多不饱和脂肪酸（PUFA）干预治疗创伤。 FADS 基因簇（11 号染色体；12-13q）内的变异在调节脂质和对损伤的炎症反应，因此可能是造成不同结果的原因。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 干预措施，例如 ω-3 PUFA，用于危重患者新型多级统计基因组模型。在 K25 期间开发的成果将深入了解遗传/表观遗传变异在 FADS 基因簇对炎症、血栓形成和代谢反应相互作用的影响拟议的研究意义重大，因为普遍缺乏适当的定量研究。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该方法是创新的，因为它尝试使用。数学和统计基因组技术来增进我们对创伤病理生理学的了解。总之，拟议的培训和研究计划将启动 Rahbar 博士作为独立 R01- 的职业生涯资助急性创伤和重症监护精准医学和营养基因组学的研究人员和领导者。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

揭示 FADS 簇内关键调控区域的 DNA 甲基化景观。

DOI：
发表时间：
2017
期刊：
影响因子：
3.7
作者：
Rahbar, Elaheh;Ainsworth, Hannah C;Howard, Timothy D;Hawkins, Gregory A;Ruczinski, Ingo;Mathias, Rasika;Seeds, Michael C;Sergeant, Susan;Hixson, James E;Herrington, David M;Langefeld, Carl D;Chilton, Floyd H
通讯作者：
Chilton, Floyd H

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

rs174537 对急性肺损伤危重患者的影响：OMEGA 随机临床试验的二次分析。

DOI：
发表时间：
2020-10
期刊：
影响因子：
0
作者：
Dosso, Beverly;Waits, Charlotte Mae K;Simms, Kelli N;Sergeant, Susan;Files, D Clark;Howard, Timothy D;Langefeld, Carl D;Chilton, Floyd H;Rahbar, Elaheh
通讯作者：
Rahbar, Elaheh

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

获得性抗凝血酶缺乏是重大创伤后静脉血栓栓塞的危险因素。

DOI：
发表时间：
2021
期刊：
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.

人类唾液、CD4 细胞和总白细胞 DNA 中 FADS 基因组区域的等位基因特异性甲基化。

DOI：
发表时间：
2018
期刊：
影响因子：
5.7
作者：
Rahbar, Elaheh;Waits, Charlotte Mae K;Kirby Jr, Edward H;Miller, Leslie R;Ainsworth, Hannah C;Cui, Tao;Sergeant, Susan;Howard, Timothy D;Langefeld, Carl D;Chilton, Floyd H
通讯作者：
Chilton, Floyd H

Gut microbiota regulates cardiac ischemic tolerance and aortic stiffness in obesity.

肠道微生物群调节肥胖患者的心脏缺血耐受性和主动脉僵硬度。

DOI：
10.1152/ajpheart.00346.2019
发表时间：
2019-09-27
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
Micah L. Battson;Dustin M. Lee;Lance C. Li Puma;Kayl E. Ecton;Keely N. Thomas;Hallie P. Febvre;A. Chicco;T. Weir;C. Gentile
通讯作者：
C. Gentile