Lefort Lab
Brown University & Rhode Island Hospital
“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” - Dr. Lefort's Research
I am very excited and grateful to focus on translational science (which is sort of where I began in biomedicine!) in one of the most exciting times in immunology: new tools to study neutrophil biology in Dr. Craig Lefort’s Lab in the Division of Surgery at Rhode Island Hospital. I am in the beginning stages of this project, but currently I am starting out by characterizing the “Journey” of a neutrophil in health and disease. My hope is to gain an understanding of how neutrophils “Know” where to go, what to do once there, and “who”, or rather, the milieu of other cell types and signaling factors are involved in this process. More to come as I learn about this amazing little cells!
My current work focuses on mechanism of neutrophil progenitor engraftment in the bone marrow. The goal is to understand if these cells could be used to treat neutropenia and neutrophil dysfunction, which are associated with increased susceptibility to severe bacterial and fungal infections. Recently, we characterized murine neutrophil progenitor cell lines (NPs) that are conditionally immortalized via HoxB8 expression and are uniquely capable of engrafting in the naïve murine host. We propose that NPs may be a therapeutic adjunct for reducing infection resulting from neutropenia or neutrophil dysfunction. To achieve this, it is first essential to understand the mechanisms of NP engraftment in the hematopoietic niche. We have observed that NPs home and/or engraft via a VLA4-independent, beta1 integrin-dependent mechanism. Further, we found that engrafted NPs proliferate and differentiate into mature neutrophils mobilized to the periphery via canonical CXCR2 signaling. My specific aims are to determine the impact of cytoreductive conditioning of host niche space via antibody-mediated depletion of Ly6G-expressing cells or busulfan-mediated HSPC ablation on NP engraftment. To further evaluate the potential translational utility of NPs, we also probe candidate integrin alpha subunits and signaling receptors to determine their role in NP engraftment. Understanding the mechanisms of engraftment of neutrophil progenitors using in vitro and in vivo murine models are crucial first steps in determining therapeutic utility.
The scientist studies the scientist! Hah! This picture is of me examining a cell culture of packaging cells used to create virus which is subsequently used to genetically modify murine neutrophil progenitor cells to determine which proteins are involved in the mechanisms of neutrophil progenitor engraftment in host bone marrow.