Biomedical Sciences Graduate Program | University of California, San Francisco

My lab focuses on how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues. Much of the work is focused on four members of this family, the epithelial-restricted integrin,avb6, and the widely expressed integrins a9b1, avb5 and avb8. avb6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGFb), that depend on distinct sequences in the b6 cytoplasmic domain. We have shown that the latter function plays a central role in tissue fibrosis, acute lung injury, protection from pulmonary emphysema, tumor invasion and in the airway hyperresponsiveness that follows chronic allergen challenge. Currently we are identifying pathways that regulate each of these responses and are using tissue specific rescue transgenes in b6 ko mice to characterize the roles of these pathways in vivo. We have also identified several components of the signaling pathways by which cells regulate integrin-dependent TGFb activation and are currently determining the injury-related stimuli that activate these pathways and working to develop rationally-designed drugs targeting this integrin for potential treatment of acute lung injury, pulmonary fibrosis, invasive carcinomas and asthma. The avb8 integrin also activates TGFb and is expressed on both lung epithelial cells and leukocytes. We are currently utilizing mice expressing a conditional null allele of the b8 subunit to examine the roles of this pathway in lung development, airway remodeling and regulation of innate and cognate immunity.

a9b1 is expressed by a wide variety of cells and recognizes at least 15 distinct ligands. a9b1 is critical for cell migration, an effect that depends on unique sequences in the a9 cytoplasmic domain. We are identifying and characterizing proteins that specifically bind to these sequences and the downstream signals that mediate enhanced migration. As a9 ko mice are not viable, we have generated mice expressing a conditional null allele to better the role of this integrin in vivo. a9 knockout mice die from a defect in lymphatic development, and we are currently working to identify the molecular mechanisms by which this integrin contributes to lymphangiogenesis and angiogenesis. a9 knockout mice also have a defect in neutrophil development due to defective signaling in response to the cytokine, GCSF, and we are currently determining the molecular details underlying this defect. avb5 is also widely expressed, but mice lacking this integrin are phenotypically normal. However, these mice are dramatically protected in multiple models of acute lung injury. We are currently identifying the mechanisms underlying this effect.

Current treatments of most common lung diseases are ineffective or toxic, in part due to limited understanding of the molecular events underlying these diseases. We are taking an unbiased approach to this problem, combining global analysis of gene expression and computational analysis of genetic loci responsible for differences in disease models in inbred strains of mice. In parallel, we are generating mice expressing null mutations of leading candidate genes identified from our screening approaches. To complement this strategy, we are part of a Bay area consortium Baygenomics that is generating a library of mouse embryonic stem cells containing inactivating mutations in random murine genes and generating selected lines of mice expressing null mutations of genes predicted to contribute to lung development or disease. Thus far, we have targeted more than 3000 individual genes and are beginning to evaluate selected lines for abnormalities in lung development and in models of acute lung injury, asthma and pulmonary fibrosis.