Message from the Vice Chair for Research
April introduces areas of investigation in our active Pulmonary and Critical Care Division. As Division Director, Dr. Shannon Carson and senior faculty oversee basic lung research in airways disease, environmental medicine, and a growing clinical trials and outcomes platform in multiple areas of pulmonary and critical care disease. Importantly, UNC maintains a longstanding and incredibly productive stake in Cystic Fibrosis research, which asks fundamental questions at the cellular and systems levels which are being translated in Phase I clinical trials. This month, Dr. Carson has asked 5 members of his Division to highlight their research. Our Chair's Corner podcast features Dr. Falk's interview with Dr. Mock about his research on Acute Respiratory Distress Syndrome.
Janet Rubin, MD
Vice Chair for Research
Jason Mock, MD, PhD
Dr. Jason Mock is interested in how the lung resolves injury and undergoes repair after damage. In acute or chronic injury the failure to regenerate the lung epithelium plays a role in such processes as pneumonia, pulmonary fibrosis, COPD, aging, and acute respiratory distress syndrome (ARDS). ARDS is a common pulmonary disease often seen and treated in intensive care units. This syndrome encompasses a spectrum of diffuse lung injury characterized by hypoxemia, capillary leakage, edema, and epithelial cell damage. Despite decades of research into the pathogenesis underlying the development of ARDS, mortality remains high. Recently there has been considerable interest in the cell types involved in repair and the regulation of these processes in the lung. One type of white blood cell, the Foxp3+ regulatory T cell (Treg), appears important in the resolution of ARDS, but how Tregs interact with the cells lining the lungs to aid lung repair is unknown.
After completing his fellowship in June 2014, Dr. Mock joined the Division of Pulmonary Diseases and Critical Care Medicine as a Clinical Instructor. Several factors drew him to UNC including the superb research environment, an outstanding group of consultants, and importantly the department’s and division’s focus on mentorship to help junior investigators develop the tools to progress to successful careers as independent investigators.
Since his faculty transition, Dr. Mock’s lab group has made exciting observations on the importance of Tregs in the repair of the alveolar epithelium. His recent K08 proposal explores lymphocyte and epithelium interactions during resolution of lung injury with the ultimate goal of improving patient outcomes in this oftentimes fatal disease.
Robert Hagan, MD, PhD
Dr. Rob Hagan’s lab studies how the immune system responds to lung infections such as influenza. After completing a PhD focused on the mammalian cell cycle, Dr. Hagan caught the immunology bug while taking care of critically ill ICU patients during his internal medicine residency. While all humans suffer from respiratory virus infections, some are mild and self-limited, and other infections result in lung damage and even death. The Hagan lab uses a combination of mouse genetics, in vitro cell culture experiments, and protein biochemistry to study how macrophages from the lung and blood respond to infection and inflammation. The lab’s current focus is on the intersection between virus-sensing pathways and proteins with which cells monitor nutrition and energy. The ultimate goal of this work is to develop host-directed therapeutics that limit infection lung damage without compromising immune responses. Similar energy and immune pathways are relevant to cancer, obesity, metabolism, liver disease, and neurodegenerative disorders. The lab is always looking for new collaborators and avenues to translate our findings into patient-based research.
When not in the lab, Dr. Hagan attends in the MICU and sees patients with a variety of pulmonary diseases at Meadowmont. Outside the lab Dr. Hagan enjoys biking and hiking with his family.
Michael Knowles, MD
Dr. Michael Knowles is a clinical and translational investigator with a long term research interest in rare genetic diseases of the lung. His initial research with Drs. Richard Boucher and John Gatzy in the early 1980s resulted in discovery of abnormal ion transport in airway epithelia of patients with cystic fibrosis (CF). This CF-related abnormality in ion transport results in defective mucociliary and cough clearance, and provided seminal insight into the pathophysiology of CF lung disease. In 1989, the molecular basis of CF lung disease was discovered to reflect biallelic (recessive) mutations in a cAMP-regulated Cl- channel (CFTR), and Dr. Knowles spent the 1990s studying correlations between different mutations in CFTR and the clinical phenotypes in CF. In 2000, Dr. Knowles was a co-founder of the International CF Gene Modifier Consortium. Subsequent studies by the Consortium have demonstrated that non-CFTR genetic variants contribute to modification of the disease phenotype, which illustrates that CF is not only a “monogenic” disorder, but also has elements of a “complex” genetic disorder. Dr. Knowles and his collaborators have translated their physiological and genetic data to develop studies of novel therapies for CF lung disease, which are ongoing.
Another focus of his research is Primary Ciliary Dyskinesia (PCD), which is another disorder with deflective mucociliary clearance reflecting mutations in genes necessary for ciliary structure and function. In 2003, Dr. Knowles and Dr. Margaret Leigh established a North American Consortium to study PCD, and these efforts resulted in development of nasal nitric oxide (nNO) as a diagnostic test for PCD, and allowed systematic characterization of the clinical phenotype in PCD. In conjunction with Maimoona Zariwala PhD, UNC investigators made major contributions to the discovery of 35 “PCD genes”, and led to the development of clinically available diagnostic genetic panels of >30 PCD genes for in this recessive, genetically heterogeneous disorder. Translation of physiological data in PCD, in conjunction with Dr. R. Boucher, has led to clinical trials of a novel inhaled agent to improve cough clearance in PCD.
More recently, Dr. Knowles and Dr. M. Leigh Anne Daniels have considered clinical phenotypes of patients with Idiopathic Bronchiectasis. These studies suggest that the pathophysiology of lung disease in some of these patients may involve abnormal bronchial connective tissue reflecting genetic variants in heritable connective tissue disorders, such as Marfan and Ehlers-Danlos Syndromes. Genetic studies are ongoing to test this hypothesis.
- An overview of published work can be found on PubMed and Google Scholar.
- Read more about Dr. Knowles and his research.
Stephen Tilley, MD
The long-term goal of Dr. Stephen Tilley’s research program is to understand the molecular mechanisms responsible for airway inflammation and airway hyperresponsiveness (AHR) in asthma. The lab investigates disease pathogenesis using human airway epithelial cells and mast cells in conjunction with animal models with targeted over-expression or deletion of candidate genes encoding enzymes and receptors of major inflammatory pathways. The lab is also interested in pre-clinical drug discovery and proof-of-concept testing of pharmacological efficacy using these models of asthma.
Presently, the lab is funded to investigate the pathogenesis of ozone-induced asthma exacerbations. The objective of this project is to elucidate the cellular and molecular mechanisms by which ozone causes airway inflammation and AHR, with the overarching goal of informing the rational design of clinical trials for asthma targeting the identified pathways.
Dr. Tilley also directs the UNC Lung Disease Models Center which serves as a core facility for faculty at UNC and neighboring institutions. The core induces lung disease and assists with phenotyping using a number of well-established and novel animal models of airway and parenchymal lung diseases including asthma, chronic rhinosinusitis, acute lung injury, and pulmonary fibrosis. For example, collaborating with scientists at the NIEHS in RTP, the core helped establish that the nuclear transcription factors ROR-α and ROR-γ are critical for the development of allergic airway inflammation. Subsequently it has been shown by other groups that ROR-α is required for the development of innate lymphoid cells type 2 (ILC2) and ROR-γ critical for Th17 lymphocyte development, two lymphocyte populations responsible for driving the pathogenesis of distinct asthma phenotypes. Recently the core has been participating in the Marisco Lung Institute’s Tobacco Center for Regulatory Science (TCORS) project to study the effects of new and emerging tobacco products on lung biology by providing the infrastructure for the in vivo exposures.
Claire M. Doerschuk, MD
Dr. Doerschuk’s research interests address pneumonia, acute lung injury and lung disease induced by tobacco smoke. Pneumonia occurs mostly commonly in both young and elderly populations and in patients who are immunosuppressed. Acute lung injury can result from pneumonia or from numerous other injuries to lungs or other organs. Dr. Doerschuk’s program focuses on understanding mechanisms underlying lung host defense and innate immunity in the lungs, particularly those that initiate the host’s responses. The mechanisms underlying the recognition of pathogens or other lung injuries, the recruitment of leukocytes, changes in vascular permeability, functions of leukocytes, and the effects of leukocytes and edema are currently active areas. Leukocyte kinetics, including neutrophil production and release from the bone marrow and their sequestration, adhesion and migration into lung tissue, change during inflammation and contribute to successful clearance of the pathogen. Leukocyte-endothelial cell interactions are critical in host defense, and the cell signaling pathways initiated by engagement of adhesion molecules by each cell type are exciting and topical. These studies utilize in vivo and in vitro cell biological, immunological, and molecular approaches.
Dr. Doerschuk’s interest in tobacco smoke-induced lung disease focuses on the toxicity of smoke and the development of chronic obstructive lung disease, both chronic bronchitis and emphysema. Chronic inflammatory and immune responses underlie the development of both aspects of this disease. She is particularly interested in acute exacerbations, which are episodes of acute inflammation on top of chronic injury due to cigarette smoke. They are often attributable to abnormal host responses to viral or bacterial infections or to environmental stimuli, including air pollution. They are important because exacerbating patients usually do not fully recover their previous lung function, and exacerbations often result in a persistent decline. Her studies utilize a wide range of translational and basic immunological and molecular tools to understand these responses.
Dr. Doerschuk’s ultimate goal and hope is to utilize this knowledge to develop therapies that enhance the inflammatory response when it is beneficial to the patient and to dampen this response when it is harmful.
Richard Boucher, MD
In collaboration with many members of the Cystic Fibrosis Center, the Marsico Lung Institute, and the Virtual Lung Group, Dr. Boucher’s lab focuses on understanding the pathogenesis of a syndrome of lung diseases called “chronic bronchitis”(CB.) In the simplest of terms, chronic bronchitis reflects a failure to clear hyperconcentrated mucus, which produces a symptom of cough, sputum production, airway inflammation, and infections. Heretofore, it has been difficult to study chronic bronchitic diseases because the mucin macromolecules that generate the biophysical properties of a transportable an enormous (> 100 MD molecular weight), and classic imaging techniques e.g. CT, and biochemical measures of sputum composition have been of limited value.
A major effort of the Virtual Lung Group and our group has been on the comprehensive genetic, biochemical, and particularly biophysical analysis of how mucus flows in health and why it adheres (“sticks”) in disease. This research has led to a novel formulation of the typography of mucus on airways surfaces, with the new view being that there are two gels on the airway surface (a model mucus gel layer and a cell surface gel layer. This model places emphasis on the concentration of mucins in the mucus layer as being the determinant of flow in health and failure to flow in disease. Importantly, the biophysical properties that govern mucin/mucus flow scale to the 2nd to 8th power of mucus concentration. This insight has led to numerous investigations into the mechanisms that produce hyperconcentrated mucus in disease and have identified hyperconcentration as a common final pathway in diseases such as cystic fibrosis, COPD, and primary ciliary dyskinesia (PCD).
The recognition that hyperconcentrated mucus produces airway muco-obstruction and the downstream symptom and pathology consequences of the CB syndrome has led to multiple translational efforts. For example, measures of mucus concentration and the concomitant biophysical forces that dominate flow verses no flow, e.g. mucus osmotic pressure, have been tested in clinical studies, and strong correlations have been found between diseases state, mucus concentration, and mucus osmotic pressure in CF and COPD. Indeed, ongoing epidemiologic studies are testing the hypothesis that mucus concentration/osmotic pressure will be the epidemiologic biochemical and biophysical counterpart of the symptom questionnaire for definition of CB. In parallel, the notion that mucin hyperconcentration drives the pathogenesis of CB diseases has led to the development of a spectrum of novel pulmonary therapies designed to rebalance the concentrations of mucus, salt, and water in mucus to establish and remove adherent mucus from the lungs and restore normal flow. Future directions of the group are focused now on the pathogenesis of asthma, as the “other” muco-obstructive lung disease. Asthma is characterized by the hypersecretion of a special secreted mucin (MUC5AC) which may confer properties to mucus that scale differently to concentration. Thus the unique genetic, biochemical, and biophysical aspects of a MUC5AC dominated asthma mucus are being studied, and the possibility that novel therapies for this class of lung diseases will be required is being investigated.