R01HL155623

Identifying mechanisms and reversibility of eosinophil-induced airway hyperinnervation in asthma - Asthma is characterized by excessive bronchoconstriction and a heightened sensitivity to inhaled irritants. Airway nerves control these responses.

Recently, we found that eosinophils, which are a defining feature of airway inflammation in a majority of asthmatics, increased sensory nerve density in humans with asthma and in mice. Increased innervation produced exaggerated neuronally-mediated reflex bronchoconstriction.

These data show that eosinophil-induced nerve remodeling has a key role in the development of excessive bronchoconstriction in asthma. The central hypothesis of this proposal is that eosinophils increase airway nerve density in asthma by releasing granule proteins that induce neurotrophins, which in turn promote nerve growth and potentiate nerve-mediated reflex bronchoconstriction.

We will test this hypothesis in three aims that will (1) determine the role of eosinophil granule proteins EPX and MBP in sensory and parasympathetic nerve remodeling, neurotrophin expression, and nerve-mediated reflex bronchoconstriction; (2) test which neurotrophins mediate eosinophil-induced nerve remodeling and reflex bronchoconstriction; and (3) determine whether airway hyperinnervation is reversed in humans with asthma by measuring airway nerves in bronchoscopic airway biopsies before and after initiation of the anti-IL5 antibody mepolizumab. Effects of eosinophil depletion will also be tested in mice with established hyperinnervation.

The ultimate goals of this study are to discover new asthma mechanisms and to identify drug targets that will prevent and/or reverse effects of nerve dysfunction in asthma.

Oregon Health & Science University

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]

Oregon United States

State-Wide

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 442% from $599,621 to $3,251,305.