Sepsis is a serious entity and the leading cause of death in the critically ill patients. It is characterized by a systemic inflammatory response syndrome (SIRS) and its associated multi-organ failure (MOF). The pathogenesis of sepsis associated SIRS/MOF is still poorly understood and therapeutic/diagnostic options remain limited. One of the remaining questions for the development of SIRS/MOF is how the focal infections are exaggerated to systemic inflammation. Based on our published and preliminary studies, we believe that exosomal-shuttle miRNAs play crucial roles in transporting inflammatory signals to the distant target cells and organs. miR-15a and miR-16 are clustered closely at the same chromosome position, thus, carrying similar cellular functions. We believe that miR-15a/16 mediate macrophage over-activation and transport the inflammatory signals to distant targets, via the macrophage released exosomes (extracellular vesicles). The generation and encapsulation of miR-15a/16 into the exosomes require PTRF, a novel lipid raft protein shuttling between plasma membrane and nuclei. Consistently, our published studies have demonstrated that deletion of PTRF protected mice from SIRS/MOF/death after CLP and deceased macrophage derived NO/ROS. In this proposal, we hypothesize that exosomal (EV)-shuttle miR-15a/16 plays crucial roles in sepsis induced SIRS and its associated MOF. Our studies potentially provide novel therapeutic and diagnostic targets for SIRS/MOF after sepsis, which is highly relevant to clinical practice. Macrophages, the first arm of defense in the immune system, play crucial roles in the transmission and amplification of inflammatory signals. Therefore, we use macrophages as the cellular models. Cecal ligation and puncture (CLP) is used as an in vivo sepsis model. We will test our hypotheses in the following specific aims:
Aim I : To determine the generation, secretion and regulation of miR-15a/16 in macrophages in vitro.
Aim II : To determine the cellular functions of miR-15a/16 in macrophages in vitro.
Aim III : To determine the functional roles of exosomal (EV)- shuttle miR-15a/16 in sepsis in vivo.

Public Health Relevance

This project will focus on the role of exosomal-shuttle miR-15a/16 in sepsis associated systemic inflammatory response. Our proposed work will potentially identify novel targets and strategies to develop therapeutic and diagnostic approaches against severe sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM111313-01
Application #
8747155
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2014-09-15
Project End
2018-05-31
Budget Start
2014-09-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Cao, Yong; Zhang, Duo; Moon, Hyung-Geun et al. (2016) MiR-15a/16 Regulates Apoptosis of Lung Epithelial Cells after Oxidative Stress. Mol Med 22:
Zhang, Duo; Lee, Heedoo; Zhu, Ziwen et al. (2016) Enrichment of selective miRNAs in exosomes and delivery of exosomal miRNAs in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol :ajplung.00423.2016
Zhang, Duo; Lee, Heedoo; Cao, Yong et al. (2016) miR-185 mediates lung epithelial cell death after oxidative stress. Am J Physiol Lung Cell Mol Physiol 310:L700-10
Lee, Heedoo; Zhang, Duo; Zhu, Ziwen et al. (2016) Epithelial cell-derived microvesicles activate macrophages and promote inflammation via microvesicle-containing microRNAs. Sci Rep 6:35250
Lee, Heedoo; Zhang, Duo; Minhas, Jasleen et al. (2016) Extracellular Vesicles Facilitate the Intercellular Communications in the Pathogenesis of Lung Injury. Cell Dev Biol 5:
Lin, Ling; Jin, Yang; Hu, Kebin (2015) Tissue-type plasminogen activator (tPA) promotes M1 macrophage survival through p90 ribosomal S6 kinase (RSK) and p38 mitogen-activated protein kinase (MAPK) pathway. J Biol Chem 290:7910-7
Moon, H-G; Qin, Z; Quan, T et al. (2015) Matrix protein CCN1 induced by bacterial DNA and CpG ODN limits lung inflammation and contributes to innate immune homeostasis. Mucosal Immunol 8:243-53
Moon, H-G; Cao, Y; Yang, J et al. (2015) Lung epithelial cell-derived extracellular vesicles activate macrophage-mediated inflammatory responses via ROCK1 pathway. Cell Death Dis 6:e2016
Lee, Seon-Jin; Zhang, Meng; Hu, Kebin et al. (2015) CCN1 suppresses pulmonary vascular smooth muscle contraction in response to hypoxia. Pulm Circ 5:716-22
Moon, Hyung-Geun; Yang, Jincheng; Zheng, Yijie et al. (2014) miR-15a/16 regulates macrophage phagocytosis after bacterial infection. J Immunol 193:4558-67

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