The vascular endothelium responds to localized infection by weakening barrier function and promoting coagulation to deliver humoral effectors of immunity and contain the spread of microbes. In systemic infection, these same protective responses become maladaptive, leading to diffuse vascular leakage and disseminated intravascular coagulation. We hypothesize that the septic endothelium drives critical disease manifestations, and we seek innovative ways to target and measure this complex process.
Aim 1 will evaluate the roles of two major endothelial cell-surface receptors, PAR1 and Tie2, whose activation can promote inflammation, thrombosis, and barrier dysfunction during sepsis. We have identified novel drug-like molecules that target PAR1 and Tie2 and synergize to achieve endothelial quiescence in the face of septic stimuli.
This aim will ask how PAR1 and Tie2 collaborate at the endothelium to ameliorate clinically relevant outcomes of sepsis.
Aim 2 will address how the endothelium contributes to septic microthromboses. In addition to evaluating PAR1 and Tie2, this aim will provide a first-in-kind systematic description of the endothelial derangements that drive the early microthromboses and late coagulopathy of sepsis by utilizing a combination of intravital microscopy in genetic mouse models and novel cell-based approaches.
Aim 3 will seek new non-invasive ways to follow the dynamic responses of the endothelium to sepsis. We have developed quantitative, real-time, humanized assays of microvascular barrier dysfunction and endothelial prothrombotic potential suitable for high-throughput analysis. Applying plasmas from one of the largest ICU cohorts of its kind, we will test the predictive performance of these assays against clinical metrics and conventional biomarkers. We will also explore the potential of these assays to gauge the efficacy of new candidate therapies. This application unites a team of investigators with complementary expertise, unique resources, and a track record of productivity and collaboration. We will pursue highly parallel aims designed to generate outstanding impact in sepsis by defining fundamental disease mechanisms, testing innovative therapeutic strategies, and developing robust new diagnostic tools focused on the endothelium.

Public Health Relevance

Sepsis is a common disorder in the critically ill that is associated with high mortality and which we cannot treat with currently available medications. Sepsis is characterized by systemic inflammation that causes the vascular endothelium to become dysfunctional, resulting in leaky blood vessels and widespread coagulation. We have developed new strategies for measuring and reversing endothelial dysfunction in sepsis and will assess the effectiveness through in vivo studies and clinical samples.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-O (S1))
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Sarkar, Rita
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Beth Israel Deaconess Medical Center
United States
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Agarwal, Anupam; Dong, Zheng; Harris, Raymond et al. (2016) Cellular and Molecular Mechanisms of AKI. J Am Soc Nephrol 27:1288-99
Jang, Cholsoon; Oh, Sungwhan F; Wada, Shogo et al. (2016) A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med 22:421-6
Flaumenhaft, Robert; Furie, Bruce (2016) Vascular thiol isomerases. Blood 128:893-901
Jain, Abhishek; Graveline, Amanda; Waterhouse, Anna et al. (2016) A shear gradient-activated microfluidic device for automated monitoring of whole blood haemostasis and platelet function. Nat Commun 7:10176
Ghosh, Chandra C; David, Sascha; Zhang, Ruyang et al. (2016) Gene control of tyrosine kinase TIE2 and vascular manifestations of infections. Proc Natl Acad Sci U S A 113:2472-7
Bekendam, Roelof H; Bendapudi, Pavan K; Lin, Lin et al. (2016) A substrate-driven allosteric switch that enhances PDI catalytic activity. Nat Commun 7:12579
Sharda, Anish; Kim, Sarah H; Jasuja, Reema et al. (2015) Defective PDI release from platelets and endothelial cells impairs thrombus formation in Hermansky-Pudlak syndrome. Blood 125:1633-42
Aisiku, Omozuanvbo; Peters, Christian G; De Ceunynck, Karen et al. (2015) Parmodulins inhibit thrombus formation without inducing endothelial injury caused by vorapaxar. Blood 125:1976-85
Milam, Katelyn E; Parikh, Samir M (2015) The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation. Tissue Barriers 3:e957508
Ghosh, Chandra C; Mukherjee, Aditi; David, Sascha et al. (2015) Angiopoietin-1 requires oxidant signaling through p47phox to promote endothelial barrier defense. PLoS One 10:e0119577

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