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.

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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Brigham and Women's Hospital
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Lee, Heedoo; Zhang, Duo; Laskin, Debra L et al. (2018) Functional Evidence of Pulmonary Extracellular Vesicles in Infectious and Noninfectious Lung Inflammation. J Immunol 201:1500-1509
Zhang, Duo; Lee, Heedoo; Wang, Xiaoyun et al. (2018) Exosome-Mediated Small RNA Delivery: A Novel Therapeutic Approach for Inflammatory Lung Responses. Mol Ther 26:2119-2130
Lee, Heedoo; Abston, Eric; Zhang, Duo et al. (2018) Extracellular Vesicle: An Emerging Mediator of Intercellular Crosstalk in Lung Inflammation and Injury. Front Immunol 9:924
Zhang, Duo; Lee, Heedoo; Haspel, Jeffrey A et al. (2017) Long noncoding RNA FOXD3-AS1 regulates oxidative stress-induced apoptosis via sponging microRNA-150. FASEB J 31:4472-4481
Zhu, Ziwen; Zhang, Duo; Lee, Heedoo et al. (2017) Macrophage-derived apoptotic bodies promote the proliferation of the recipient cells via shuttling microRNA-221/222. J Leukoc Biol 101:1349-1359
Lee, Heedoo; Zhang, Duo; Rai, Ashish et al. (2017) The Obstacles to Current Extracellular Vesicle-Mediated Drug Delivery Research. J Pharm Pharm 4:156-158
Lee, Heedoo; Zhang, Duo; Wu, Jingxuan et al. (2017) Lung Epithelial Cell-Derived Microvesicles Regulate Macrophage Migration via MicroRNA-17/221-Induced Integrin ?1 Recycling. J Immunol 199:1453-1464
Zhang, Duo; Lee, Heedoo; Zhu, Ziwen et al. (2017) Enrichment of selective miRNAs in exosomes and delivery of exosomal miRNAs in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 312:L110-L121
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
Zhu, Ziwen; Zhang, Duo; Lee, Heedoo et al. (2016) Caenorhabditis elegans: An important tool for dissecting microRNA functions. Biomed Genet Genom 1:34-36

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