Despite the increased understanding of the complex pathophysiology of sepsis, severe sepsis and septic shock still have very high significant morbidity and mortality. As such, there is an urgent unmet medical need for an effective novel therapy for sepsis patients. A balanced immune response is an essential element of a successful host defense after infection. However, excessive production of pro-inflammatory mediators or cytokines may cause further tissue injury. The autonomic nervous system reflexively regulates inflammatory responses in real time. In the previous grant cycle, we showed that down-regulation of ghrelin, a gut-brain hormone, is partially responsible for sepsis-induced hepatic injury. Ghrelin's beneficial effects are mediated by the sympathetic and parasympathetic nervous systems to regulate the inflammation reaction in sepsis. Recently, we discovered that cold-inducible RNA-binding protein (CIRP) is upregulated in an animal model of sepsis and patients with sepsis, while ghrelin attenuates CIRP levels in animals that underwent sepsis. Administration of recombinant murine CIRP (rmCIRP) in healthy animals induces acute inflammation and causes tissue injury. In addition, anti-rmCIRP antibodies improve survival in sepsis animals. We have determined that TLR4 serves as the CIRP receptor. By using GFP-CIRP expression plasmid, we demonstrated CIRP translocation from the nucleus to cytoplasm after endotoxin stimulation. Furthermore, norepinephrine directly upregulates CIRP expression, while nicotine decreases endotoxin-induced CIRP expression in isolated macrophages. Thus, we hypothesize that the protective effect of ghrelin on sepsis-induced organ injury is at least in part mediated through the autonomic nervous system by controlling the production and release of a novel proinflammatory mediator, CIRP. Accordingly, four specific aims are proposed: (1) to further determine the detrimental effect of CIRP release in sepsis;(2) to further confirm that the beneficial effect of ghrelin in sepsis is mediated through down- regulation of CIRP;(3) to define the mechanism by which neurotransmitters regulate CIRP release at the cellular level;and (4) to develop anti-CIRP therapeutic agents for treating sepsis. The proposed studies should open up a new research arena for the development of innovative therapeutics for patients with sepsis and septic shock.

Public Health Relevance

Sepsis is one of the leading causes of death in intensive care units. A recent epidemiologic study estimated that more than 750,000 people develop sepsis each year and over 210,000 people succumb to this overwhelming inflammation reaction induced by infection in the United States annually. Given the intensive and prolonged care necessary to treat patients with sepsis, it costs $16.7 billion nationally and the economic burden is profound. Thus, there is an urgent unmet medical need for an effective therapy for treating patients with sepsis. Our innovative approach of discovering the novel proinflammatory mediator, cold-inducible RNA-binding protein, is pioneering in the inflammation research field. This finding will lead to the development of a new class of therapeutic agents against cold shock proteins for effectively treating such a critical clinical condition.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053008-18
Application #
8716767
Study Section
Special Emphasis Panel (ZRG1-SBIB-W (02))
Program Officer
Dunsmore, Sarah
Project Start
1995-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
18
Fiscal Year
2014
Total Cost
$337,000
Indirect Cost
$137,000
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
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Aziz, M; Jacob, A; Wang, P (2014) Revisiting caspases in sepsis. Cell Death Dis 5:e1526
Zhou, Mian; Yang, Weng-Lang; Ji, Youxin et al. (2014) Cold-inducible RNA-binding protein mediates neuroinflammation in cerebral ischemia. Biochim Biophys Acta 1840:2253-61
Matsuda, Akihisa; Yang, Weng-Lang; Jacob, Asha et al. (2014) FK866, a visfatin inhibitor, protects against acute lung injury after intestinal ischemia-reperfusion in mice via NF-*B pathway. Ann Surg 259:1007-17
Aziz, Monowar; Yang, Weng-Lang; Matsuo, Shingo et al. (2014) Upregulation of GRAIL is associated with impaired CD4 T cell proliferation in sepsis. J Immunol 192:2305-14
Giangola, Matthew D; Yang, Weng-Lang; Rajayer, Salil R et al. (2013) Growth arrest-specific protein 6 attenuates neutrophil migration and acute lung injury in sepsis. Shock 40:485-91
Qiang, Xiaoling; Yang, Weng-Lang; Wu, Rongqian et al. (2013) Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med 19:1489-95
Matsuda, Akihisa; Jacob, Asha; Wu, Rongqian et al. (2013) Milk fat globule--EGF factor VIII ameliorates liver injury after hepatic ischemia-reperfusion. J Surg Res 180:e37-46
Lufrano, Maria; Jacob, Asha; Zhou, Mian et al. (2013) Sphingosine kinaseýýý1 mediates endotoxemiaýýýinduced hyperinflammation in aged animals. Mol Med Rep 8:645-9
Saito, Yu; Shimada, Mitsuo; Utsunomiya, Tohru et al. (2013) The protective effect of adipose-derived stem cells against liver injury by trophic molecules. J Surg Res 180:162-8

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