Dean Sheppard, MD, PhD

Affiliated

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,??v?6, and the widely expressed integrins ?9?1, ?v?5 and ?v?8. ?v?6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGF?), that depend on distinct sequences in the ?6 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 ?6 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 TGF?? 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 ?v?8 integrin also activates TGF? and is expressed on both lung epithelial cells and leukocytes. We are currently utilizing mice expressing a conditional null allele of the ?8 subunit to examine the roles of this pathway in lung development, airway remodeling and regulation of innate and adaptive immunity.

?9?1 is expressed by a wide variety of cells and recognizes at least 15 distinct ligands. ?9?1 is critical for cell migration, an effect that depends on unique sequences in the ?9 cytoplasmic domain. We are identifying and characterizing proteins that specifically bind to these sequences and the downstream signals that mediate enhanced migration. As ?9 ko mice are not viable, we have generated mice expressing a conditional null allele to better the role of this integrin in vivo. ?9 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. ?9 knockout mice also have a defect in neutrophil development due defective signaling in response to the cytokine, GCSF. This interaction also regulates the interaction of hematopoeitic stem cells with components of the bone marrow stroma. We are currently determining the molecular details underlying this interaction. ?v?5 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. ?v?5 contributes to the development of lung injury and tissue edema at other sites by regulating reorganization of the actin cytoskeleton in contractile stress fibers. We are currently identifying the mechanisms underlying this effect.