The Role of Integrins AlphaVBeta3 and AlphaVBeta5 in Acute Lung Injury

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DESCRIPTION (provided by applicant): This proposal details a 5-year Mentored Clinical Scientist Development Award (K08) program designed to assist Dr. George Su in achieving independent status as an academic investigator. Dr. Su is interested in elucidating mechanisms critical to the development of acute lung injury (All). He has recently published work implicating integrin avps as a central regulator of lung vascular permeability and pulmonary endothelial barrier function-both considered pathologic hallmarks of ALL Integrin av(35 co-localizes with another integrin, avp3, at focal adhesions. Both integrins recognize the same extracellular matrix ligand vitronectin. Clustering of both integrins appears to be inducible by edemagenic agonists. Despite these similarities, inhibition of avps and avps have opposite effects on agonist-induced pulmonary endothelial permeability: inhibition of avps is enhancing, while inhibition of avp5 is protective. Dr. Su's recent studies suggest that avps and avp5 differentially regulate cytoskeletal arrangement in pulmonary endothelial cells; avps appears to be required for cortical actin formation (barrier-enhancing), while avp5 appears to be required for formation of transcytoplasmic stress fibers (associated with increased paracellular permeability). In this proposal, Dr. Su outlines a plan to map the critical domains of avps and avps that are required for regulation of agonist-induced pulmonary endothelial permeability, define direct and functional associations of avps and avps to signaling intermediates previously identified to be important for cortical actin and stress fiber formation, and to describe the effects of pS, P5, and double ps/p5 subunit deficiency in a mouse ventilation-induced lung injury model of ALL Furthermore, to assist with his career development, Dr. Su has assembled a K08 advisory panel of highly-regarded physician-scientists; has developed a detailed curriculum of didactic training courses, scientific conferences, and seminars; and has secured the full commitment of the UCSF Department of Medicine and the Division of Pulmonary and Critical Care Medicine. Full access to all necessary resources will allow Dr. Su to take advantage of K08 support towards building a productive and successful academic career as a physician-scientist in pulmonary medicine. Relevance: ALI is a syndrome associated with close to 75,000 deaths a year in the United States alone. Effective pharmacologic therapies are not currently available. Dr. Su's previous work and preliminary data suggest that integrins avps and avp5, specific members of the integrin family of cell surface receptors, may regulate pulmonary vascular permeability, an important hallmark of ALI. These proposed studies may support the intriguing potential of these integrins as therapeutic targets to modulate lung vascular permeability in disease states like ALI. (End of Abstract)