The proposal continues our objective to elucidate the molecular events that control acute systemic inflammation, a highly lethal process. In the previous grant cycle, we discovered a Toll like receptor (TLR) - driven, temportally-defined, epigenetic program in innate immunity macrophages and neutrophis, which directs the course of acute systemic inflammation. This process modifies chromatin structure to repress or activate distinct functional sets of genes, thus generating distinct phenotypic phases. Others and we have shown that bioenergy shifts also occur in innate immunity cells during acute systemic inflammation. This application develops the unified concept that modifications in bioenergetics integrate with epigenetics to direct the phase shifts of acute inflammation. We propose two specific aims:
Aim 1) To define the connections between bio-energy and epigenetics. We will use a cell model that reproduces TLR4-dependent phase shifts to: a) delineate gene-specific chromatin modifications;b) determine protein-protein interactions;c) assess metabolic profiles by mass spectroscopy;and c) translate our concept to human normal and sepsis blood leukocytes.
Aim 2) To test effects of modifying bio-energy and epigenetic shift on clinical outcomes. We will us a murine model of sepsis to: a) define bio-energy and epigenetic phase shifts, using biochemical and genetic methods to analyze plasma and isolated leukocytes from spleen, peritoneum, and bone marrow;and b) use pharmacologic and genetic approaches to determine whether modifying to adaptive phase alters microvascular inflammation and survival. Our result will broadly impact the field of inflammation by providing new insight on how acute inflammation is orchestrated, and inform novel therapies.

Public Health Relevance

Acute systemic inflammation is a major health care problem, killing ~300,000/ yr in USA. No effective therapies exist for altering the inflammatory component of the disease. This research will provide new insight into the molecular events that coordinate the temporal features of sepsis, and enable design of therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI065791-09S1
Application #
8883829
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dong, Gang
Project Start
2005-07-01
Project End
2016-02-29
Budget Start
2014-08-22
Budget End
2015-02-28
Support Year
9
Fiscal Year
2014
Total Cost
$35,121
Indirect Cost
$9,978
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Millet, Patrick; Vachharajani, Vidula; McPhail, Linda et al. (2016) GAPDH Binding to TNF-α mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism. J Immunol 196:2541-51
Vachharajani, Vidula T; Liu, Tiefu; Wang, Xianfeng et al. (2016) Sirtuins Link Inflammation and Metabolism. J Immunol Res 2016:8167273
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
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. (2015) Resveratrol attenuates microvascular inflammation in sepsis via SIRT-1-Induced modulation of adhesion molecules in ob/ob mice. Obesity (Silver Spring) 23:1209-17
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
Liu, Tie Fu; Vachharajani, Vidula; Millet, Patrick et al. (2015) Sequential actions of SIRT1-RELB-SIRT3 coordinate nuclear-mitochondrial communication during immunometabolic adaptation to acute inflammation and sepsis. J Biol Chem 290:396-408
Hoth, J Jason; Wells, Jonathan D; Jones, Sarah E et al. (2014) Complement mediates a primed inflammatory response after traumatic lung injury. J Trauma Acute Care Surg 76:601-8; discussion 608-9
Vachharajani, Vidula; Liu, Tiefu; McCall, Charles E (2014) Epigenetic coordination of acute systemic inflammation: potential therapeutic targets. Expert Rev Clin Immunol 10:1141-50
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

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