Grant: $1,496,674 - National Institutes of Health - Sep. 11, 2009
0% voted satisfied - 100% voted not satisfied - 2 vote(s) cast
Award Description: The fundamental roles of innate and adaptive host responses are to recognize and eradicate invading antigens, pathogens or altered self components with the purpose of restoring tissue integrity and homeostasis. While resolution can occur when the host response is normal, an exogenous insult cannot be contained when a critical host factor is inactivated, dysregulated, becomes dysfunctional or genetic and/or environmental factors conspire to result in chronic lung disease. In our proposal, this critical host factor is surfactant protein A (SP-A), a protein that lines the epithelial surfaces in the lung. We have chosen to focus upon this factor, since normal SP-A can attenuate allergic inflammation, but SP-A that is altered or abnormal as a consequence of genetic polymorphisms and/or oxidative changes has abrogated ability to defend the host from environmental insults leading to excessive bronchoconstriction and allergic inflammation. Our preliminary studies in vitro, in animal models of airway inflammation and in patients with asthma have identified specific defects in the role of SP-A in the innate immune response that contribute to the persistence or exacerbation of asthma and allergic disease. The central hypothesis to be tested is that SP-A which normally regulates innate immunity and protects the host from persistence and exacerbation of asthma, is dysfunctional in asthma. We present three interrelated projects employing animal models and translational studies in humans that will determine how SP-A bridges the innate and adaptive immune systems in the host response to exogenous insults in asthma. These projects will employ specific environmental challenges (infection and ozone exposure) to test the ability of SP-A to modulate allergic inflammation in asthma, and whether allelic variants of SP-A, insufficient quantities or oxidation are responsible for dysfunction of SP-A in asthma. Project 1 will evaluate the ability of human SP-A from asthmatic subjects and allelic variant SP-A to modulate the innate and adaptive responses to infection and ozone exposure, respectively, in the human macrophage and airway epithelial cell. Project 2 will employ murine models of ovalbumin sensitization and challenge to determine if asthmatic SP-A and allelic variants of SP-A effectively modulate inflammaton induced by an infectious challenge. Project 3 will determine whether a specific SP-A polymorphisms modulates differential sensitivity to ozone exposure in asthma (physiologic and mechanical), and whether SP-A itself undergoes oxidation during in vivo ozone exposure in humans. We bring together our team of investigators with expertise in murine, biochemical and translational studies; our collective expertise and the synergy among projects will enable progress and high potential for success in the elucidation of SP-A-mediated host defense mechanisms critical to innate immune modulation of allergic inflammation in asthma.
Project Description: See Award Description
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 11, 2009. Help expand these official descriptions using the wiki below.