Sepsis is a leading cause of death in ICUs. Sepsis is characterized by an intense systemic inflammatory response activating a cascade of proinflammatory events resulting in coagulation, leukocyte dysregulation and host tissue damage. Therapeutic approaches to the treatment of sepsis are largely supportive and no specific pharmacologic therapies are available that protect from neutrophil-mediated tissue damage. As the inflammatory response in sepsis is complex and comprised of multiple redundant and overlapping signaling pathways, rather than being limited to a single pathway, we chose to identify specific control points used by multiple pathways. We identified Protein Kinase C-delta (PKC?) as a critical regulator of the inflammatory response. We have shown that PKC? is activated in the lungs of septic rodents and that inhibition of PKC? decreases neutrophil influx and exerted a lung protective effect. These studies indicate an important regulatory role for PKC? controlling proinflammatory signaling and neutrophil activation and migration but do not address specific mechanisms. A key step in neutrophil-mediated tissue damage is the migration of activated neutrophils across the vascular endothelium. In the proposed studies, we will determine the mechanism by which PKC? regulates neutrophil activation and migration during sepsis. We hypothesize that PKC? activity plays a significant role in regulating neutrophil-endothelial crosstalk, neutrophil migration, and vascular endothelial damage and will determine whether targeting PKC? activity offers a unique therapeutic strategy for the control of neutrophil migration and activation in sepsis. We will use our newly developed novel bio-inspired microfluidic assay (a single assay that enables the capture of the entire neutrophil migration cascade in a synthetic microvascular network mimicking in vivo physiological conditions) in conjunction with intravital microscopy in a mouse model of sepsis (cecal ligation and puncture, CLP) to determine the role of PKC? in regulating individual steps in neutrophil migration through inflamed vasculature and the in vivo effects of genetic and pharmacologic inhibition of PKC?.
Aim 1 will identify the mechanisms by which PKC? regulates the crosstalk between neutrophils and endothelial cells through control of the expression of ligands and receptors required for neutrophil rolling, adhesion and transmigration.
Aim 2 will use PKC? deletion studies to ascertain the role of PKC? in vivo (intravital microscopy) and in vitro (novel microfluidics assay) in leukocyte rolling, adhesion and migration in the microvascular networks. Adoptive transfer studies will determine if PKC? expressed in hematopoietic cells is a critical component of sepsis-induced neutrophil migration.
Aim 3 will determine the role of PKC? in regulating vascular endothelial permeability and endothelial cell damage during sepsis. These studies will provide important mechanistic insights into the pathogenesis of sepsis and will identify potential therapeutic strategies for decreasing the morbidity and mortality associated with this disease.

Public Health Relevance

Sepsis is one of the leading causes of morbidity and mortality in intensive care units. Inappropriate influx of neutrophils across the vascular endothelium has been implicated in the pathogenesis of this disease. We propose to use a series of novel in vivo and in vitro models to test the hypothesis that control of a specific enzyme, Protein kinase C delta (PKC?), will prevent tissue injury and offer a unique therapeutic target for the treatment o sepsis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Dunsmore, Sarah
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Temple University
Internal Medicine/Medicine
Schools of Medicine
United States
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Liverani, Elisabetta; Mondrinos, Mark J; Sun, Shuang et al. (2018) Role of Protein Kinase C-delta in regulating platelet activation and platelet-leukocyte interaction during sepsis. PLoS One 13:e0195379
Soroush, Fariborz; Tang, Yuan; Zaidi, Hasan M et al. (2018) PKC? inhibition as a novel medical countermeasure for radiation-induced vascular damage. FASEB J :fj201701099
Soroush, Fariborz; Tang, Yuan; Guglielmo, Kimberly et al. (2018) Protein Kinase C-Delta (PKC?) Tyrosine Phosphorylation is a Critical Regulator of Neutrophil-Endothelial Cell Interaction in Inflammation. Shock :
Zheng, Xiaoyi; Soroush, Fariborz; Long, Jin et al. (2017) Murine glomerular transcriptome links endothelial cell-specific molecule-1 deficiency with susceptibility to diabetic nephropathy. PLoS One 12:e0185250
Soroush, Fariborz; Zhang, Ting; King, Devon J et al. (2016) A novel microfluidic assay reveals a key role for protein kinase C ? in regulating human neutrophil-endothelium interaction. J Leukoc Biol 100:1027-1035