Cell migration is central to many biological and pathological processes, including embryogenesis, tissue repair and regeneration as well as cancer and the inflammatory response. Inflammatory recruitment of leukocytes is critical in initiation and progression of a wide range of cardiovascular diseases including vasculitis and atherosclerosis. Integrin LFA-1 is a critical component in the effective trafficking of leukocytes. In various pathologic conditions, sustained or dysregulated integrin activation causes aberrant leukocyte infiltration and tissue damage. Therefore, studies of the functions of the integrins and the regulation of cell adhesiveness and migration through them are of great importance in enhancing our ability to develop better- targeted and more effective anti-inflammatory therapies. Although a great deal of information has been learned about the sequential action of chemoattractants and adhesion molecules that mediate the early steps in leukocyte extravasation, including tethering, rolling and firm adhesion, little is known about dynamic and spatial regulation of integrin activation during leukocyte polarization and migration. The central hypothesis of the proposed study is that a small subpopulation of cell surface LFA-1 become activated and localize to the leading edge of polarized cells to mediate migration, which are then switched to low affinity at the uropod allowing efficient tail retraction. Using dynamic fluorescence resonance energy transfer (FRET) assay, we will visualize temporo-spatial LFA-1activation during lymphocyte chemotaxis. The effectsof selective inhibition of the high affinity LFA-1 using a newly developed monoclonal antibody and its advantages over conventional non-selective anti-adhesion agents will be tested. Integrins transduce bidirectional signals across the plasma membrane through conformational changes (affinity regulation) and clustering in the cell membrane (avidity regulation) that regulate extracellular adhesiveness and intracellular signaling. The effects of selective inhibition of the two distinctive mechanisms on lymphocyte migration will be investigated with small molecule antagonists. Finally, we will determine the distinct signaling networks associated with LFA-1 activation at the leading edge, and de-activation at the trailing edge during dynamic lymphocyte migration. This study will enhance our understanding of pathogenic factors that are relevant to a wide range of inflammatory diseases and may reveal new approaches for therapeutic intervention.
| Capece, Tara; Kim, Minsoo (2016) The Role of Lymphatic Niches in T Cell Differentiation. Mol Cells 39:515-23 |
| Lim, Kihong; Hyun, Young-Min; Lambert-Emo, Kris et al. (2015) Neutrophil trails guide influenza-specific CD8? T cells in the airways. Science 349:aaa4352 |
| Knowlden, Sara A; Capece, Tara; Popovic, Milan et al. (2014) Regulation of T cell motility in vitro and in vivo by LPA and LPA2. PLoS One 9:e101655 |
| Lerman, Yelena V; Lim, Kihong; Hyun, Young-Min et al. (2014) Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin ?3?1-dependent. Blood 124:3515-23 |
| Stevenson, Catherine; de la Rosa, Gonzalo; Anderson, Christopher S et al. (2014) Essential role of Elmo1 in Dock2-dependent lymphocyte migration. J Immunol 192:6062-70 |
| Xu, Yuexin; Hyun, Young-Min; Lim, Kihong et al. (2014) Optogenetic control of chemokine receptor signal and T-cell migration. Proc Natl Acad Sci U S A 111:6371-6 |
| Overstreet, Michael G; Gaylo, Alison; Angermann, Bastian R et al. (2013) Inflammation-induced interstitial migration of effector CD4? T cells is dependent on integrin ?V. Nat Immunol 14:949-58 |
| Hyun, Young-Min; Sumagin, Ronen; Sarangi, Pranita P et al. (2012) Uropod elongation is a common final step in leukocyte extravasation through inflamed vessels. J Exp Med 209:1349-62 |
| Baker, Christina M; Comrie, William A; Hyun, Young-Min et al. (2012) Opposing roles for RhoH GTPase during T-cell migration and activation. Proc Natl Acad Sci U S A 109:10474-9 |
| Sarangi, Pranita P; Hyun, Young-Min; Lerman, Yelena V et al. (2012) Role of ?1 integrin in tissue homing of neutrophils during sepsis. Shock 38:281-7 |
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