Poor prognosis of severe sepsis is associated with impaired microcirculation, multiple organ injury and disseminated intravascular coagulation (DIC) as a result of interdependent mechanisms of systemic intravascular inflammation, vascular leakage, microvascular thrombosis, and thrombocytopenia. Currently, no drug is available to concomitantly treat these events in sepsis. We recently discovered an important role for VWF/GPIb-IX- and integrin-dependent platelet adhesion and thrombus formation in sepsis (Yin ATVB 2013), and that G?/13 family of heterotrimeric G proteins play critical roles in integrin outside-in signaling in platelets (Gong et al, Science 2010, Shen et al Nature 2013) and in vWF secretion by endothelial cells (Rusu et al Blood 2014). G?/13 also negatively regulates cadherin function (Meigs JBC 2002) and increases endothelial permeability. In addition, we have identified NOS1-dependent regulation of Suppressor of Cytokine Signaling (SOCS1) expression in monocytes/macrophages (Baig et al, Science Signaling, in revision) as a critical determinant of sepsis-induced vascular inflammation and hyperpermeability. Here, we will test the hypotheses that sepsis can be effectively treated by concomitant anti-thrombotic, anti-inflammatory and anti- hyperpermeability therapy with novel agents that do not cause hemorrhage and vascular leakage. We have generated novel inhibitory peptides of G?/?AP interaction that inhibit endothelial VWF secretion as well as inhibitors of G?-integrin and vWF-GPIb-IX interactions that potently inhibit thrombosis without adversely inducing hemorrhage (Shen et al, Nature 2013;Yin et al, ATVB 2013;Rusu et al., Blood 2013). We propose to (1) determine the therapeutic effect of inhibiting GPIb and G?/13/integrin signaling in sepsis;(2) determine the role of G?-dependent endothelial cell VWF secretion in sepsis-induced microthrombosis;and (3) interfere with the inflammatory response that induces endothelial hyperpermeability in sepsis concomitantly with anti-thrombotic therapy. This study will not only provide novel therapeutic concepts in sepsis, but also translate these concepts into new anti-sepsis drugs and treatments.

Public Health Relevance

Systemic bacterial infection, or sepsis, is associated with poor prognosis due to impaired microcirculation and disseminated intravascular coagulation because of interdependent mechanisms of systemic intravascular inflammation, vascular leakage, microvascular thrombosis, and thrombocytopenia. Currently, no drug is available to concomitantly treat these events and mortality in septic patients remains extremely high. Based on our recent discoveries of important roles of VWF-GPIb-IX/integrin-dependent platelet thrombus formation in sepsis, the role and mechanisms of VWF secretion in sepsis, and the role of Ga13 in integrin signaling and thrombosis, we generated novel peptide-based inhibitors for use in treating thrombosis, vascular leakage, and inflammation with the ultimate goal of reducing mortality due to sepsis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL125356-01
Application #
8803056
Study Section
Special Emphasis Panel (ZHL1-CSR-O (S1))
Program Officer
Sarkar, Rita
Project Start
2014-09-15
Project End
2019-05-31
Budget Start
2014-09-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$647,554
Indirect Cost
$241,564
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Yan, Zhibo; Wang, Zhen-Guo; Segev, Nava et al. (2016) Rab11a Mediates Vascular Endothelial-Cadherin Recycling and Controls Endothelial Barrier Function. Arterioscler Thromb Vasc Biol 36:339-49
He, Chenxia; Hart, Peter C; Germain, Doris et al. (2016) SOD2 and the Mitochondrial UPR: Partners Regulating Cellular Phenotypic Transitions. Trends Biochem Sci 41:568-77
Ju, Lining; Chen, Yunfeng; Xue, Lingzhou et al. (2016) Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals. Elife 5:
Delaney, M Keegan; Kim, Kyungho; Estevez, Brian et al. (2016) Differential Roles of the NADPH-Oxidase 1 and 2 in Platelet Activation and Thrombosis. Arterioscler Thromb Vasc Biol 36:846-54
Estevez, Brian; Kim, Kyungho; Delaney, M Keegan et al. (2016) Signaling-mediated cooperativity between glycoprotein Ib-IX and protease-activated receptors in thrombin-induced platelet activation. Blood 127:626-36
Jiang, Ying; Sverdlov, Maria S; Toth, Peter T et al. (2016) Phosphatidic Acid Produced by RalA-activated PLD2 Stimulates Caveolae-mediated Endocytosis and Trafficking in Endothelial Cells. J Biol Chem 291:20729-38
Urner, M; Schläpfer, M; Herrmann, I K et al. (2015) Insight into the beneficial immunomodulatory mechanism of the sevoflurane metabolite hexafluoro-2-propanol in a rat model of endotoxaemia. Clin Exp Immunol 181:468-79
Shen, Bo; Estevez, Brian; Xu, Zheng et al. (2015) The interaction of Gα13 with integrin β1 mediates cell migration by dynamic regulation of RhoA. Mol Biol Cell 26:3658-70
Schläpfer, Martin; Piegeler, Tobias; Dull, Randal O et al. (2015) Propofol increases morbidity and mortality in a rat model of sepsis. Crit Care 19:45
Baig, Mirza Saqib; Zaichick, Sofia V; Mao, Mao et al. (2015) NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1. J Exp Med 212:1725-38