We study cell adhesion receptors, called the integrins, and how they regulate a variety of biological processes. Adhesion, or binding, to external surfaces, ligands and other cells is a fundamental property of all biological cells and modulates signaling and function of each cell. In response to certain signals, or cues, cells activate and use surface-expressed integrin molecules to selectively and specifically bind to extracellular ligands in a process known as “inside-out” signaling. Conversely, integrin-mediated cellular adhesion induces certain intracellular signaling in cells that modulates biological functions of cells (a process referred to as “outside in signaling”). We are using the knowledge gained from structural changes in integrins upon activation and from subsequent activation induced intracellular signaling pathways as a way to learn about the biology of various cell types. We are also applying this knowledge to better devise novel therapeutics to treat a variety of diseases.
As a model system, one set of projects is focused on leukocytes (white blood cells) and the integrin CD11b/CD18 (also known as Mac-1, CR3 and αMβ2), which is highly expressed on these cells. Leukocytes play a central role in inflammation. We have recently identified a novel group of small molecules that allosterically bind to and enhance CD11b/CD18-dependent cell adhesion. Using these compounds (that we refer to as “leukadherins”) in a variety of in vitro and in vivo model systems, we recently established that pharmacologic enhancement of leukocyte cell adhesion is a novel and unique mechanism for reducing inflammation and inflammatory injury. Current studies in the lab are looking at developing leukadherins as novel anti-inflammatory therapeutics for use in the clinic in the future to treat a variety of diseases, including lupus, lupus nephritis, vascular inflammation, restenosis as well as cancer.
In another model system, we are studying the adhesion receptors expressed in the kidney podocytes and their role in maintaining a healthy kidney. Podocytes are specialized cells that form the final filtration barrier in the kidney. Podocyte adhesion to the extracellular matrix, via their integrins, is central to their health. We are studying the role of various integrins in podocytes and their associated signaling pathways in health and disease in a variety of kidney disease model systems, including focal segmental glomerulo nephritis (FSGS), membranous nephropathy, autoimmune nephritis and diabetic nephropathy.
Finally, we have a keen interest in identifying novel agents as potential therapeutics using high throughput, high content screening methodologies. Towards that end, we have developed a number of high-quality, novel cell-based assays and technologies in the laboratory and are using them to screen compound collections.