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Overview

The Medoff Laboratory studies the mechanisms of lung injury, inflammation and fibrosis in the pathophysiology of several important pulmonary diseases, including asthma, idiopathic pulmonary fibrosis, lung transplant rejection, chronic obstructive pulmonary disease and respiratory viral infections such as influenza. Using animal models of disease, cutting edge molecular biology techniques, integrative genomics and translational studies in humans, the Medoff Laboratory investigates the molecular mechanisms involved in the development of lung inflammation and fibrosis in order to reveal novel aspects of lung biology and immunity, and to identify potential therapeutic targets for these disorders.

The laboratory is affiliated with the Division of Pulmonary and Critical Care Medicine in the Department of Medicine at Massachuestts General Hospital, as well as the Center for Immunology and Inflammatory Diseases, the Andrew M. Tager Fibrosis Center and the Division of Rheumatology, Allergy, and Immunology.

Research Projects

Airway epithelium and inflammation

The airway epithelium is a key modulator of the immune response in the lung through its interactions with innate immune cells such as dendritic cells and innate lymphoid cells. My research program has looked at the role of the airway epithelium and dendritic cells in the establishment of the adaptive immune response in allergic airway inflammation. Using animal models of disease and in vitro assays we have established a critical role of CARMA3 for the immune response to allergens in the lungs. In other work we have established the key role for dendritic cells and macrophages for the recruitment of neutrophils and T cells into the lung.

Lung Fibrosis

Despite recent approval of two new therapies, many patients with idiopathic pulmonary fibrosis (IPF) continue to have progressive disease, impaired exercise capacity, and poor quality of life.  Clearly more effective and targeted therapy for IPF could have a positive impact on the well-being of the numerous people affected by this disease. Endothelial cell dysfunction and exaggerated vascular permeability are cardinal components of the initial pathways activated in response to repetitive lung injury. We and others have demonstrated that endothelial cell dysfunction and unresolved vascular leak in the lung is not simply a consequence of pulmonary fibrosis, but a central contributor to its progression.  Despite these observations, mitigating the vascular responses that lead to hyperpermeability and fibrosis have received relatively little investigative attention. The lab seeks to (1) understand the roles of endothelial ROCK1 and ROCK2 in the vascular response to lung injury and in the development of pulmonary fibrosis; and (2) to investigate whether the endothelial-specific delivery of ROCK inhibitors can halt the progression of lung fibrosis.

Translational Human Studies

Our lab has developed a translational research program that recruits human subjects to study the pathogenesis of various inflammatory lung diseases. The program was initially focused on defining the mechanisms of T cell recruitment and activation in the lungs of human subjects with allergic asthma, HIV and COPD, and after lung transplantation. More recently we have begun studies focused on defining the innate immune cell profile and changes in epithelial cell functions in the human lung in health and disease. Samples are obtained from human subjects using bronchoalveolar lavage and airway brushings, and the samples are studied using advanced flow cytometry, CyTOF, RNA sequencing and in vitro cellular assays. The subjects are further classified using advanced imaging techniques such as HRCT-PET and optical coherence tomography to better define their pulmonary anatomy and physiology.

T Cell Regulation

We are interested in the mechanisms controlling T cell activation and effector functions in asthma, pulmonary infections and lung transplantation. Specifically, we use mouse models of disease, genetically modified mice, cellular immunology techniques, and translational human studies to characterize the role of effector and regulatory T cells in health and disease. We have demonstrated the importance of CARMA1 in the development of allergic airway inflammation and regulatory T cell development, the role of Tim3 in modulating the response to influenza infection and transplant rejection, and the role of Mst1 in T cell development and activation.

Publications

Full list of publications


Research Group Members

Jehan Alladina, MD

Katharine Black, MD

Patricia Brazee, PhD

Roxene Clarke

Matthew Drummond

Francesca Giacona

Rachel Knipe, MD

Tristan Kooistra, MD

Amanda Logue

Yang Yang, PhD