? ? 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) ? ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL083097-02
Application #
7471369
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2007-07-16
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$124,200
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Su, George; Atakilit, Amha; Li, John T et al. (2013) Effective treatment of mouse sepsis with an inhibitory antibody targeting integrin *v*5. Crit Care Med 41:546-53
Su, George; Atakilit, Amha; Li, John T et al. (2012) Absence of integrin ?v?3 enhances vascular leak in mice by inhibiting endothelial cortical actin formation. Am J Respir Crit Care Med 185:58-66
Bhattacharya, M; Su, G; Su, X et al. (2012) IQGAP1 is necessary for pulmonary vascular barrier protection in murine acute lung injury and pneumonia. Am J Physiol Lung Cell Mol Physiol 303:L12-9