Research

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Our laboratory focuses on two main research program. (1) Studying the effects of cigarette smoke (CS) exposure in the pathogenesis of airway and lung diseases such as chronic obstructive pulmonary disease (COPD) using preclinical genetic mouse models and human biosamples. (2) Studying novel immune regulators in the lung during respiratory infections. (3) Translating basic research findings in human patient population. 

COPD

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COPD is a composite entity that includes chronic bronchitis and emphysema, is a leading cause of death in the world, and is a disease that is in need of new treatments. One of the goal of our laboratory is to investigate the interaction between CS and respiratory virus infection in the pathogenesis of COPD and identify novel therapeutic targets for this respiratory disease. It has been long thought that the frequent respiratory infections in COPD patients are due to their depressed immune function. 

Our studies have revealed that CS-exposed hosts have an over-exaggerated immune reaction to viral infections. Frequent acute COPD exacerbations correlate with increased rate of disease progression and more loss of lung function in COPD especially if it is due to viral infections. Our studies have shown that CS exposure has an impressive ability to regulate the innate immunity in the lung after influenza virus and respiratory syncytial virus (RSV) infection. CS enhances the inflammation, alveolar destruction and airway fibrosis caused by influenza virus and RSV. These effects are mediated by type I interferon and RIG-like helicase antiviral innate immune pathway. CS exposure also results in the induction of interleukin-15 in the setting of these respiratory infections. 

We hypothesize that these novel mechanistic pathways may explain the heightened inflammatory response and worsening lung functions in COPD patients with multiple virally-induced exacerbations, and the chronic lung inflammation seen in stable COPD patients. We have also translated our findings by studying these immune mediators in patients infected with various respiratory viruses and have thus far collected >200 human biosamples.

Immune Regulators

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Our laboratory also investigates the novel role of chitinases and chitinase-like molecules in various pulmonary infections. Using genetic mouse models, we have established the importance of chitinase and chitinase-like molecules in the mechanism of lung inflammation and injury after infection, specifically after Streptococcuspneumoniae infection. Chitinase 3-like 1 (Chi3l1) [YKL-40 in human] is a prototypic chitinase-like protein of the 18-glycosyl hydrolase gene family.Its level is elevated in the circulation and tissues of patients with diseases characterized by inflammation and tissue repair.

Our recent novel findings demonstrate that Chi3l1 is a potent inflammasome regulator that augments macrophage bacterial killing through inhibiting caspase-1 dependent macrophage pyroptosis and controlling the damage associated molecular pattern, ATP and the P2X7 receptor responses in pneumococcal lung infection. We believe that these molecules involved in the inflammasome pathway are important in acute lung injury which will be studied by the proposed grant submission.

Lung Infections

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Our overall approach is to establish translational studies to better understand the role of infections in human lung diseases in our patient population. With the help of residents and fellows, and more recently a research assistant, we were able to enroll ~350 biospecimens from patients who have been infected with various respiratory viruses since 2009 admitted to Yale New Haven Hospital. This work has already yielded important findings confirming our basic research data as well as helped us develop new hypotheses that we are testing in the mouse models. We are also in the midst of recruiting patients with bacterial pneumonia, bacteremia and sepsis, and collecting blood and airway specimens. These patient oriented studies helped me obtain translational grants through Yale Center of Clinical Investigation (YCCI).

Microbiome

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The human body, including the lung, is made up of a complex community of microbial pathogens. These microbial communities are highly variable in particular individuals and compose as much as 150 distinct microbial families. These microbes are commensals but can be harmful to the host, and can be routinely detected in respiratory specimens. Our lab is interested in the role of these microbial communities in the homeostatic and regulatory response to incoming stimuli such as cigarette smoke exposure or respiratory infections. We are also studying the role of antibiotics use on microbiome in lung inflammation and injury response.