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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM099807-02
Application #
8500394
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2012-07-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$335,651
Indirect Cost
$108,860
Name
Wake Forest University Health Sciences
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Vachharajani, Vidula T; Liu, Tiefu; Brown, Candice M et al. (2014) SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome. J Leukoc Biol 96:785-96
Vachharajani, Vidula; Liu, Tiefu; McCall, Charles E (2014) Epigenetic coordination of acute systemic inflammation: potential therapeutic targets. Expert Rev Clin Immunol 10:1141-50