R01HL164563

Progenitors, mechanisms of differentiation, and functions of lung M cells - M cells have been shown to sample luminal antigens and use transcytosis to deliver these antigens to underlying antigen presenting dendritic cells. Thus, they serve as key regulators of mucosal immunity.

Despite the vast body of literature on the immunologic role of M cells in other mucosal organs, airway M cells have only recently been described and almost no functional or molecular characterization has been performed. We present the first single cell transcriptomes of murine airway M cells and identify airway M cell signaling cascades that regulate inflammation.

We have discovered that airway M cells occur as solitary cells in the murine trachea and as patches in the murine small airway, and we report the directed differentiation of human airway M cells from primary human airway epithelium. Finally, we demonstrate that airway M cells are induced by the administration of the signaling factor RANKL, treatment with lipopolysaccharide (LPS), and influenza infection.

Interestingly, M cells can occur as solitary cells, but in the setting of physiologic stimuli like LPS or influenza infection, patches of M cells are associated with lymphoid follicles suggesting a functional epithelial-immune unit.

In this grant application, we propose to use our combined expertise in stem cell biology, epithelial biology, lung inflammation, and influenza infection to define the functional biology of lung M cells. We will start by defining the cellular origins of murine and human airway M cells.

We have now generated a comprehensive battery of murine genetic driver lines for lineage tracing all the cells of airway epithelium. Herein, we propose to deploy this set of murine lines, for the first time, in order to precisely define all the putative parental epithelial cell types that can give rise to M cells. We will also clarify the role of RANKL-RANK signaling pathways in murine models of inflammation.

Finally, to define airway M cell functions, we constructed a new SOX8-CreER driver mouse that allows us to specifically label, genetically modify, and ablate M cells. We will integrate these genetic reagents with existing murine disease models to elucidate the functional roles of M cells in models of airway inflammation and influenza infection.

Lastly, we will dissect the molecular mechanisms of two candidate chemokines that govern M cell-immune cell interactions using genetic and pharmacological manipulation in combination with a novel tracheal explant and lung slice live imaging platform.

The General Hospital Corporation

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Boston, Massachusetts 021142621 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 300% from $795,168 to $3,180,672.