In vivo function of integrins and molecular basis of lung diseases 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 five members of this family, the epithelial-restricted integrin, αvβ6, and the widely expressed integrins α9β1, αvβ5, αvβ3 and αvβ8. αvβ6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGFβ), that depend on distinct sequences in the β6 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. We have also identified several components of the signaling pathways by which cells regulate integrin-dependent TGFβ activation and are currently determining the injury-related stimuli that activate these pathways.

The αvβ8 integrin also activates TGFβ. Mice we have generated lacking this integrin on dendritic cells develop auto-immunity and colitis, suggesting αvβ8-mediated TGFβ activation on dendritic cells can negatively regulate adaptive immunity. We are currently characterizing the mechanisms underlying this effect, the mechanisms by which this process is regulated during the induction of adaptive immune responses, and the relevance of this pathway in various models of immune-mediated disease, including allergic asthma.

α9β1 is expressed by a wide variety of cells and recognizes at least 15 distinct ligands. α9β1 is critical for cell migration, an effect that depends on unique sequences in the α9 cytoplasmic domain. We are identifying and characterizing proteins that specifically bind to these sequences and the downstream signals that mediate enhanced migration. As α9 ko mice are not viable, we have generated mice expressing a conditional null allele to better the role of this integrin in vivo. α9 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. α9 ko mice also have a defect in lung development, with impaired secondary septation, the final step in development of mature alveoli. We are currently characterizing which α9 expressing cells are critical for this process and the molecular mechanisms by which α9 contributes to alveolar development.

αvβ5 is also widely expressed, but mice lacking this integrin develop normally. However, these mice are dramatically protected in multiple models of acute lung injury. This phenotype is explained, at least in part, by a central role for this integrin in regulating reorganization of the actin cytoskeleton in activated endothelial cells. We are currently examining the mechanisms by which this integrin, and its close relative, αvβ3, exert opposing effects on actin organization, vascular permeability and tissue edema.

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 3500 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.