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.
Obesity and sepsis are major causes of morbidity throughout the world. Results from this research may improve our understanding of the interplay of these inflammatory diseases and guide novel therapies.
|Wajih, Nadeem; Basu, Swati; Ucer, Kamil B et al. (2018) Erythrocytic bioactivation of nitrite and its potentiation by far-red light. Redox Biol 20:442-450|
|Wang, Xianfeng; Buechler, Nancy L; Long, David L et al. (2018) Cysteine thiol oxidation on SIRT2 regulates inflammation in obese mice with sepsis. Inflammation :|
|Long, David; Wu, Hanzhi; Tsang, Allen W et al. (2017) The Oxidative State of Cysteine Thiol 144 Regulates the SIRT6 Glucose Homeostat. Sci Rep 7:11005|
|Wajih, Nadeem; Basu, Swati; Jailwala, Anuj et al. (2017) Potential therapeutic action of nitrite in sickle cell disease. Redox Biol 12:1026-1039|
|Buechler, Nancy; Wang, Xianfeng; Yoza, Barbara K et al. (2017) Sirtuin 2 Regulates Microvascular Inflammation during Sepsis. J Immunol Res 2017:2648946|
|Wang, Xianfeng; Buechler, Nancy L; Martin, Ayana et al. (2016) Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. PLoS One 11:e0160431|
|Wang, XianFeng; Buechler, Nancy L; Yoza, Barbara K et al. (2016) Adiponectin treatment attenuates inflammatory response during early sepsis in obese mice. J Inflamm Res 9:167-174|
|Vachharajani, Vidula T; Liu, Tiefu; Wang, Xianfeng et al. (2016) Sirtuins Link Inflammation and Metabolism. J Immunol Res 2016:8167273|
|Millet, Patrick; Vachharajani, Vidula; McPhail, Linda et al. (2016) GAPDH Binding to TNF-? mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism. J Immunol 196:2541-51|
|Smith, Lane M; Wells, Jonathan D; Vachharajani, Vidula T et al. (2015) SIRT1 mediates a primed response to immune challenge after traumatic lung injury. J Trauma Acute Care Surg 78:1034-8|
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