Monocytes are the predominant leukocyte in atherosclerotic plaque and may contribute both to the development and instability of atherosclerotic lesions. Chemoattractant cytokines, or chemokines, are small, secreted proteins that activate monocytes, and recent data suggest they play a key role in the development of atherosclerosis in animal models. One mechanism by which chemokines contribute to leukocyte recruitment is by enhancing the avidity of leukocyte integrins for locally expressed adhesion molecules. However, the pathways by which chemokines activate integrins to augment adhesion are poorly understood. Based on our preliminary data that PI 3-Kinase (PI 3-K) is necessary for chemokine-triggered arrest in an in vitro flow model, we have recently proposed studies to test the hypothesis that PI 3-K works through downstream activation of substrates which include Akt, cytohesin- I and integrin linked kinase (ELK). With the Independent Scientist Award (K02), the applicant will use time protected by this mechanism to build upon his recently proposed in vitro studies. The applicant will place an intensive research focus towards extending his present line of signaling investigation in vivo. Using adenoviral gene transfer to monocytic cells, we will examine the role of PI 3-K and its downstream targets in murine models of leukocyte trafficking. We will study adhesion of genetically manipulated monocytes to activated endotheliurn in a mouse dorsal skin window model and assess homing of monocytes to atherosclerotic lesions in Apo E mice. The applicant is a principal investigator in the new MGH Center for Immunology and Inflammatory Disease, which provides a rich intellectual environment to establish the groundwork for this line of animal investigation. As evidenced by seven years of vascular biology research, the applicant remains firmly committed to a long-term career in basic science investigation.
| Friedrich, Erik B; Sinha, Sumita; Li, Ling et al. (2002) Role of integrin-linked kinase in leukocyte recruitment. J Biol Chem 277:16371-5 |
| Meiler, Steffen E; Hung, Rebecca R; Gerszten, Robert E et al. (2002) Endothelial IKK beta signaling is required for monocyte adhesion under laminar flow conditions. J Mol Cell Cardiol 34:349-59 |
