Bioenergetic and Epigenetic Reprogramming by Obesity in Sepsis

脓毒症中肥胖引起的生物能和表观遗传重编程

• 批准号: 8638031
• 负责人: Vidula Vachharajani
• 金额: $ 32.67万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638031
• 关键词: Acute; Adherence; Affect; Agonist; Animals; Bioenergetics; Biological Assay; Biosensing Techniques; Biosensor; Cause of Death; Cell Communication; Cells; Chromatin; Chronic; Clinical; Country; Data; Disease; E-Selectin; Endothelial Cells; Epigenetic Process; Gene Expression; Human; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory Response; Injury; Intercellular adhesion molecule 1; Interleukin-1; Intestines; Knockout Mice; Leukocytes; Lipopolysaccharides; Liver; Mediator of activation protein; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mus; Myelogenous; Niacinamide; Nicotinamide Mononucleotide; Obese Mice; Obesity; Organ; Outcome; Peritoneal Macrophages; Plasma; Production; Pyruvate; Radiolabeled; Reaction; Research; Resolution; Resveratrol; Sepsis; Signal Pathway; Signal Transduction; Staging; TNF gene; Testing; Tissues; Toll-like receptors; Western Blotting; chromatin immunoprecipitation; cytokine; human IRAK3 protein; improved; in vivo; inhibitor/antagonist; insight; intravital microscopy; macrophage; mortality; novel; radiotracer; research study; response; septic; toll-like receptor 4

DESCRIPTION (provided by applicant): Emerging data support that changes in cellular bioenergetics, metabolism and gene expression are integrated during acute and chronic inflammatory diseases. A prominent example of this interaction occurs in obesity, where reduced levels of NAD+ biosensor sirtuin 1 (SirT1) promote chronic inflammation. Obesity substantially increases morbidity and mortality of acute inflammatory sepsis. In contrast with obesity, sepsis increases SirT1 expression, which coordinates a shift from early to adaptive inflammatory responses by modifying chromatin plasticity. The objective of this proposal is to determine how obesity-induced changes in cellular bioenergetics affect systemic microvascular inflammation and multi organ injury associated with sepsis. We hypothesize that obesity worsens sepsis inflammation by dysregulating Sirt1-dependent reprogramming of the inflammatory response. To test this, we have developed sepsis models in normal and obese mice that can track microvascular inflammation in vivo. We will use these models and three aims to evaluate our concept: Aim 1 will test that obesity amplifies early responses and delays or extends adaptation of microvascular and tissue inflammatory responses during sepsis. Aim 2 will test that obesity modifies SirT1-dependent gene expression during the inflammatory response of sepsis. Aim 3 will test that modifying SirT1 or NAD+ alters sepsis inflammatory responses and survival. Completing this study will 1) provide insight into the interplay between chronic and acute inflammatory diseases; and 2) show whether Sirt1 provides a critical NAD+ biosensing axis for integrating metabolic and epigenetic reprogramming during the early and adaptation stages of sepsis.

描述(由申请人提供)：新出现的数据支持细胞生物能量学、新陈代谢和基因表达的变化在急性和慢性炎症性疾病期间是整合的。这种相互作用的一个突出例子发生在肥胖症中，NAD+生物传感器sirtuin 1(SirT1)水平的降低促进了慢性炎症。肥胖大大增加了急性炎症性脓毒症的发病率和死亡率。与肥胖相比，脓毒症增加了SirT1的表达，SirT1通过改变染色质的可塑性来协调从早期到适应性炎症反应的转变。这项建议的目的是确定肥胖引起的细胞生物能量学变化如何影响全身微血管炎症和与脓毒症相关的多器官损伤。我们假设肥胖通过失调Sirt1依赖的炎症反应重编程而加重脓毒症炎症。为了测试这一点，我们在正常和肥胖小鼠中建立了脓毒症模型，可以跟踪体内的微血管炎症。我们将使用这些模型和三个目标来评估我们的概念：目标1将测试在脓毒症期间肥胖会放大早期反应，延迟或延长微血管和组织炎症反应的适应。目的2验证在脓毒症炎症反应过程中，肥胖改变SirT1依赖基因的表达。目的3将测试修改SirT1或NAD+改变脓毒症炎症反应和生存。完成这项研究将1)深入了解慢性和急性炎症性疾病之间的相互作用；以及2)表明Sirt1是否提供了一个关键的NAD+生物传感轴，用于在脓毒症的早期和适应阶段整合代谢和表观遗传重新编程。