Bioenergetic and Epigenetic Reprogramming by Obesity in Sepsis

描述（由申请人提供）：新出现的数据支持细胞生物能量学、代谢和基因表达的变化在急性和慢性炎症性疾病期间被整合。这种相互作用的一个突出例子发生在肥胖症中，其中NAD+生物传感器sirtuin 1（SirT 1）水平降低会促进慢性炎症。肥胖显著增加急性炎性脓毒症的发病率和死亡率。与肥胖相比，脓毒症增加了SirT 1的表达，通过改变染色质可塑性，协调从早期到适应性炎症反应的转变。本研究的目的是确定肥胖诱导的细胞生物能量学变化如何影响全身性微血管炎症和脓毒症相关的多器官损伤。我们推测肥胖通过Sirt 1依赖性炎症反应重编程失调导致脓毒症炎症。为了测试这一点，我们在正常和肥胖小鼠中开发了脓毒症模型，可以跟踪体内微血管炎症。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将测试肥胖放大早期反应并延迟或延长脓毒症期间微血管和组织炎症反应的适应。目的2将测试肥胖在脓毒症的炎症反应过程中改变SirT 1依赖性基因表达。目的3将测试修饰SirT 1或NAD+改变脓毒症炎症反应和存活。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; 2）显示Sirt 1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编程。

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.