Research in the Campbell Lab is focused on understanding cell communication on a molecular level. In order to respond to their environment, cells must be able to relay external signals into the cell (outside-in signaling) as well as transmit internal signals out (inside-out signaling). Integrins are a diverse family of membrane proteins that signal bidirectionally and are critical for accurate cell communication. These uniquely shaped and versatile receptors undergo large-scale conformational changes to relay signals across the cell membrane. The integrin family is made up of 24 different — though structurally related — proteins that have varying tissue distributions and functions, allowing them to take part in a vast array of cellular processes. Integrin dysregulation has been associated with a myriad of pathologies including autoimmune, cardiac, pulmonary and blood diseases as well as cancer and infectious diseases; however few approved therapeutics exist. We utilize a broad range of methods in structural biology, biophysics, protein engineering, biochemistry, and cell biology to shed light on the molecular details of integrin signaling.  Concurrently, we are developing cryo-electron microscopy methods—both computational and biochemical—to boost structural detail and more thoroughly characterize the dynamics of integrin receptors.

Integrin

Integrin αvβ8 plays important roles in fibroinflammatory processes and anti-tumor immunity. In particular, the immunosuppressive function of regulatory T cells, which is a major mechanism of tumor immune evasion, is determined by αvβ8-mediated activation of transforming growth factor (TGF-β). Although TGF-β has therapeutic potential, its ubiquitous expression has hindered drug development due to off-target effects. Targeting αvβ8 integrin-mediated TGF-β activation provides a specific therapeutic strategy without the accompanying toxicities.

Method Development

Over the past decade, cryo electron microscopy (cryoEM) has been established as a leading method for structural determination. Macromolecules ranging from small proteins to large multi-component assemblies can now be visualized in atomic detail using this technique. CryoEM enables studying protein dynamics (which is an integral part of their function), receptor/drug interactions, and macromolecular complexes in their native cellular environments. Ongoing method development bringing in collaborative insight from computer vision, chemistry, and material science will continue to propel the limits of cryoEM forward.