The primary focus of Dr. Lefort's lab is on elucidating the mechanisms of leukocyte integrin activation. Integrins are adhesion receptors that are critical for leukocyte trafficking by allowing them to interact tightly with the blood vessel wall. The affinity of integrins is highly regulated by proteins that bind to their short cytoplasmic tails and change the structure of the integrin extracellular domains -- a process called "inside-out" activation. We discovered that two of these proteins, Talin-1 and Kindlin-3, play distinct roles in regulating beta-2 integrin activation. We are now further dissecting the molecular details of integrin activation and investigating how the roles of integrins (and their activation) varies across leukocyte subsets and in different vascular beds throughout the body.
Biography
Dr. Craig Lefort is an Assistant Professor of Surgery (Research) in the Department of Surgery at The Warren Alpert Medical School of Brown University. He received his B.S. in Biomedical Engineering from Columbia University in 2001 and his Ph.D. in the same field from the University of Rochester in 2008.
In 2010, Dr. Lefort completed his postdoctoral work in cellular and molecular immunology under the mentorship of Dr. Minsoo Kim in the Department of Microbiology and Immunology at the University of Rochester in Rochester, NY. Later that year, he was invited to join the laboratory of Dr. Klaus Ley as a postdoctoral fellow at the La Jolla Institute for Allergy & Immunology in La Jolla, CA, where his research focused on studying the regulation of LFA-1, an integrin receptor that plays essential roles in leukocyte trafficking and immunity. In 2012, he was awarded a 4-year Scientist Development Grant from the American Heart Association.
In 2013, Dr. Lefort joined the Division of Surgical Research at Rhode Island Hospital and was appointed to the rank of an Assistant Professor of Surgery (Research) where he continues his research on the molecular mechanisms by which leukocytes regulate the structure and activation state of LFA-1.
Research Overview
During infection or injury, white blood cells (leukocytes) must exit from the circulation to reach sites in the tissue where they are needed to mount an immune response. My lab's focus is on the neutrophil, a type of innate immune cell that is the first to mobilize from the circulation to mount the inflammatory response. The recruitment of neutrophils occurs by a cascade of interactions with the endothelial cell lining of the blood vessel wall that precedes their migration into the tissue. We use biophysical and molecular engineering methods to dissect the mechanisms of neutrophil trafficking and how they engulf and destroy microbes. Our research also uses an innovative cellular tool - conditionally-immortalized neutrophil progenitors - to gain the technical capacity for genetic engineering in order to identify novel aspects of neutrophil function and thereby develop strategies for combating drug-resistant bacterial and fungal infections.
We are also deeply interested in understanding how the neutrophil response is altered in the critically ill. We have found that the systemic response to hemorrhagic shock, as occurs following traumatic injury, renders neutrophils unable to efficiently sense and migrate to sites of infection. At the same time, neutrophils can become prematurely activated under conditions of systemic immune dysfunction and cause damage to host tissues. Our research aims to develop strategies to restore neutrophil function and minimize tissue injury associated with hyperinflammation.
Funded Research
R35GM124911, NIH/NIGMS, 2017-2028: "Selective modulation of neutrophils in critical illness"
R03AI130526, NIH/NIAID, 2017-2018: "A murine model of Pseudomonas aeruginosa pneumonia secondary to hemorrhagic shock"
Oh-Zopfi Pediatric Research Pilot Grant, Women & Infants Hospital, 2017-2018: "A Genetic Screen to Identify Mechanisms of Neutrophil Phagocytosis of Candida"
Pilot Project, CardioPulmonary Vascular Biology COBRE, 2015-2016: "Integrin activation regulates neutrophil trafficking during bacterial pneumonia"
Scientist Development Grant, American Heart Association, 2012-2016: "Mechanisms of LFA-1 Conformational Activation in Neutrophils"