Adenovirus modulation of pulmonary inflammation

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DESCRIPTION (provided by applicant): This proposal outlines a five-year program to develop a career in academic medicine. The principal investigator will focus his efforts on developing the skills and experience in virology and immunology necessary to become an independent investigator. This program is based on a study of adenovirus pathogenesis, in particular the interactions between respiratory viral infection, pulmonary inflammation and airway hyperreactivity. Kathy Spindler, Ph.D., is an established investigator in the field of adenovirus pathogenesis and is a recognized expert in the mouse adenovirus type 1 (MAV-1) model used in this proposal. She has successfully trained postdoctoral fellows and graduate students and will mentor the principal investigator's scientific development. The principal investigator's scientific and career development will be enhanced by interactions with the members of his advisory committee, comprised of a group of investigators at the University of Michigan who are leaders in the fields of virology and pulmonary immunology. Their expertise will provide relevant support for the proposed research plan. Their vast mentoring experience will provide solid career guidance for the principal investigator. Research will focus on the interplay between adenovirus infection and host chemokine responses in the lung. The proposal uses MAV-1, providing the advantage of using a pathogen in its natural host, allowing for studies of both acute and persistent infection, and allowing the use of a vast array of reagents including knockout and transgenic mice. The proposed experiments will define the role of chemokine responses in the control of acute and persistent adenovirus infection and will determine the ability of Dersistent adenovirus infection to modulate host responses in the lung. The specific aims are: 1) define the roles of CCL5 and CCR5 in the pathogenesis of MAV-1 respiratory infection, and 2) determine whether Dersistent MAV-1 infection modulates pulmonary inflammation and airway hyperreactivity induced by subsequent inflammatory stimuli. The University of Michigan provides the ideal setting for this training program, with a wealth of physical and intellectual resources that maximize the principal investigator's Dotential to successfully establish a career as an independent investigator. Information resulting from this research will substantially increase our understanding of how adenovirus causes respiratory disease. In addition, these experiments will aid in solidifying links between persistent adenovirus infection and chronic lung diseases such as asthma and chronic obstructive pulmonary disease and have the potential to lead to virus-targeted therapies for the prevention or management of these conditions. (End of Abstract)