This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Leukocytes are essential mediators of host defense. During inflammation, large numbers of leukocytes leave the bloodstream and traffic into the tissue where they rapidly and effectively locate and destroy invading microorganisms. Although leukocytes are critical for normal host defense, many diseases are characterized by uncontrolled inflammation. Inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), multiple sclerosis and atherosclerosis, have an enormous impact on the quality of life for millions of North Americans and cost billions of dollars annually in direct health care costs and lost productivity. Understanding the mechanisms that regulate inflammation is critical for creating therapeutics that can treat these diseases without adversely affecting host defense. My laboratory examines the mechanisms that regulate leukocyte recruitment and activation during inflammation.Leukocytes interact with endothelial cells under flow conditions found in the vasculature. Leukocyte recruitment occurs in a step-wise manner with leukocytes first rolling along the endothelium. This is followed by leukocyte activation, firm adhesion and transmigration. In studies that laid the foundation for our current work, we showed that eosinophil transmigration across the endothelium only occurred under flow conditions. We showed that vascular adhesion molecules serve as mechanotransducers, converting the mechanical force of leukocyte binding under flow conditions into signals that alter endothelial cell function. ERK MAP kinase, focal adhesion kinase (FAK), paxillin, calpain and the actin cytoskeleton were all involved in this process. These findings led me to initiate a collaboration with Dr. Oldenbourg and Dr. Smith at the Marine Biological Laboratories in Woods Hole, MA.Use of the Biocurrents Research Center:I used the facilities and resources in the BRC from January to July 2007 and these facilities were essential to the research I performed during my sabbatical. First and foremost were the tissue culture facilities. My work uses primary human endothelial cells and leukocyte cell lines. These cells require the use of a biosafety cabinet, CO2 incubators and related equipment and supplies. These were all made available to me within the BRC. In addition, reagents and fluorescent markers were also made available to me. I also made extensive use of the imaging chambers available within the BRC. Finally, the expertise of the individuals within the Center was instrumental in establishing new collaborations and providing insight into the data we were generating. This center provided the resources that were critical to the success of my sabbatical at the MBL. We are continuing to pursue this research area, and publications stemming from this work will acknowledge the support of the BRC. Invited Speaker, Brown University, Providence, RI June 2007Guest Speaker, Div of Hemostasis and Thrombosis, Harvard Medical School Cambridge, MA June 2007
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