Mechanisms of Force Fluctuation-Induced Relengthening in Airway Smooth Muscle

University Of Chicago, Chicago IL

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Abstract

DESCRIPTION (provided by applicant): A four year training program for the development of an academic career in airway smooth muscle biology is outlined in this proposal. The principal investigator, a pulmonologist trained to treat both adults and children, is an Instructor in the Section of Pediatric Pulmonary Medicine at the University of Chicago. Her immediate goal is to expand upon her skills as a basic scientist by combining muscle physiology, mechanics, and molecular biology principles to address airway smooth muscle function and its potential role in disease. The long term goal is to become an outstanding investigator who skillfully examines the nuances of smooth muscle physiology, exploring unique and important questions in this field. Drs. Julian Solway and Richard Mitchell will co-mentor the principal investigator's scientific and career development. Dr. Solway is an expert in airway biology and smooth muscle physiology, as well as an exceptional mentor and role model. He is committed to fostering the principal investigator's career development and ultimate independence. Dr. Mitchell is an internationally known smooth muscle physiologist and a valuable resource for guidance in experimental design and techniques. In addition, an Advisory Committee of accomplished scientists in muscle physiology and molecular biology will oversee the scientific training and career development. The proposed studies focus on identifying molecular mechanisms that regulate force fluctuation-induced relengthening (FFIR) in airway smooth muscle. The key premises underlying this proposal are that 1) breathing helps maintain normal airway caliber in the face of bronchoconstriction, and 2) understanding the molecular mechanisms underlying this response will suggest new strategies for designing novel interventions to augment this powerful endogenous bronchodilation mechanism. Hyperpnea antagonizes constrictorinduced airflow obstruction in both people and animal models and it is very likely that FFIR of airway smooth muscle accounts for this anti-bronchoconstrictor effect of breathing. Therefore, it is of considerable interest to know what mechanisms determine FFIR, and how smooth muscle might be manipulated to accentuate this phenomenon. Potentially, this approach could hold promise as a novel treatment for asthma. The goal of this proposal is to further our understanding of airway smooth muscle biology with the anticipation that such knowledge will lead to novel therapeutic strategies for diseases such as asthma (End of Abstract)