My lab is interested in the process of inflammation, where white blood cells leave the blood vessels to enter tissues, and blood vessels become leaky to water, proteins and other molecules. Inflammation is necessary for normal immunity to microorganisms, but if it persists, or is unregulated, can contribute to many human diseases including heart disease, diabetes, arthritis, and allergies. We use molecular biology, biochemistry, and advanced microscopy techniques to study inflammation.
Inflammation and the endothelial barrier:
The endothelial cells which line blood vessels are critical in maintaining a barrier between blood and tissues. The endothelial monolayer closely regulates the passage of leukocytes, macromolecules, nutrients and waste products. During inflammation, endothelial barrier function is reduced, leading to accumulation of leukocytes and leakage of inflammatory molecules into target tissue. Similarly, hematogenously disseminated infections must breach the endothelial barrier to gain access to underlying tissues. While inflammation is a necessary response to pathogens and tissue damage, when the endothelial barrier becomes chronically dysregulated it is associated with prevalent tissue injury and serious disorders such as many diseases associated with premature birth, preeclampsia, septic shock, cerebral palsy, atherosclerosis, asthma, diabetes, and autoimmunity. Control of inflammation is therefore central to many clinical interventions, and reversing the loss of endothelial barrier function during inflammation has significant therapeutic value.
Our lab uses immunology, molecular and cell biology techniques to study endothelial cells and leukocytes and their interaction as they respond to pro- and anti-inflammatory signals. We measure endothelial barrier function in monolayer permeability assays, and use immunofluorescence microscopy and protein biochemistry to study the molecular machinery of its regulation. Current studies are focused on the endothelial cytoskeleton and its role in stabilizing cell junctions between endothelial cells. We also study the process of leukocyte-endothelial interaction and transmigration, using live-cell microscopy in a model of physiologic blood flow over cultured endothelial cells. These imaging studies led to the identification of transitory adhesive structures formed between adherent leukocytes and endothelium, through which transmigration (diapedesis) occurs. Another area of interest is the interaction of pathogens such as Candida with endothelial cells. Adhesion and invasion of endothelium by yeast is critical for development of systemic Candidiasis, and identifying the molecular and cellular mechanisms will help understand the pathogenesis of this disease.
The Shaw lab is located at Women and Infant's Hospital in the Kilguss building, next to Alpert Medical School. I run the Kilguss molecular biology and imaging core in the Department of Pediatrics at WIH, and our lab routinely helps other biomedical researchers with technical or scientific issues. Because of this, we offer a learning environment for molecular and cell biology and its application to research into human disease.
1996-1998 NIDDK/NIH (PI) Individual National Research Service Award (Postdoctoral), F32DK009427
"Co-culture of Epithelial Cells and Mucosal Lymphocytes". Total direct costs: $70,600.
2000-2002 NIDDK/NIH (PI) K01 Mentored Scientist Research Award, K01DK002798
"Vascular-Endothelial Cadherin Function in Inflammation". Total direct costs: $263,000.
2008-2010 NCRR/NIH (Target Investigator) COBRE for Perinatal Biology
"Adhesion and Invasion of Human Endothelial cells by Candida Parapsilos".
2011-2013 NHLBI/NIH (PI) R21, R21HL093561 "Cytoskeletal Regulation of endothelial barrier function by WAVE2".
1999- North American Vascular Biology Organization
2000- American Association for the Advancement of Science
2000- American Society for Investigative Pathology
2001- American Association of Immunologists