Atherosclerotic vascular disease remains one of the most common causes of death in the United States. The broad goal of the proposed studies is to generate a better understanding of the mechanisms of this disease process. Atherosclerosis is an inflammatory disease. It is mediated in part by monocytes that are recruited into the vessel wall by adhesion molecules, including E- and P-selectin. Two 1(1,3)-fucosyltransferases, FucT-IV and FucT-VII, participate in the synthesis of active E- and P- selectin ligands on leukocytes. Thus, expression of these fucosyltransferases, and therefore selectin ligand activity, may regulate monocyte trafficking into the vessel wall and development of atherosclerosis. The experimental goal of this proposal is to test the hypothesis that monocyte-specific FucT-dependent selectin ligand activity modulates the development of atherosclerosis. FucT- dependent changes in atherosclerotic lesion pathology will be assessed in the low density lipoprotein receptor (LDL-R)-deficient mouse model of atherosclerosis. FucT activity in LDL-R(-/-) mice will be deleted globally and in a monocyte specific manner using gene targeting strategies, as well as reconstituted in a monocyte-specific manner using transgenesis. FucT-dependent changes in atherosclerosis in vivo will be correlated with FucT-dependent monocyte selectin ligand activity measured in a flow chamber in vitro.
The specific aims of this proposal are to: 1) Quantify atherosclerotic lesion size, and determine the qualitative alterations of the lesion in LDL-R(-/-) mice in which FucT-IV, or FucT-VII, or both FucT-IV and FucT-VII are deleted. 2) Determine the cellular adhesion parameters that enable FucT-IV- and/or FucT-VII-dependent monocyte tethering and rolling on E- or P-selectin under shear. 3) Define the selectin ligand-dependent monocyte/macrophage- specific contribution to atherogenesis by quantifying lesion size and determining the qualitative alterations of the lesion in LDL-R(-/-) mice with (a) monocyte-specific deletion of selectin ligand activity, and in (b) mice in which monocyte-specific expression of selectin ligand activity has been reconstituted by transgenesis. Together, the proposed experiments will determine the functional role of FucT-IV and/or FucT-VII in generating the selectin ligand activity necessary for atherogenesis. The experiments will also determine the quantitative and qualitative monocyte-specific selectin-dependent contributions to atherogenesis. This knowledge will contribute to the development of improved or novel preventive strategies, diagnostic procedures, and therapeutic options for atherosclerosis, which will ultimately reduce the morbidity and mortality associated with the disease and its sequelae.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090823-05
Application #
8213658
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2008-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$325,215
Indirect Cost
$102,465
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Wang, Huili; Morales-Levy, Maria; Rose, Jason et al. (2013) ?(1,3)-Fucosyltransferases FUT4 and FUT7 control murine susceptibility to thrombosis. Am J Pathol 182:2082-93
Duan, JinZhu; Lee, Yueh; Jania, Corey et al. (2013) Rib fractures and death from deletion of osteoblast ?catenin in adult mice is rescued by corticosteroids. PLoS One 8:e55757
Ojogun, Nore; Barnstein, Brian; Huang, Bernice et al. (2011) Anaplasma phagocytophilum infects mast cells via alpha1,3-fucosylated but not sialylated glycans and inhibits IgE-mediated cytokine production and histamine release. Infect Immun 79:2717-26
Willis, Monte S; Townley-Tilson, W H Davin; Kang, Eunice Y et al. (2010) Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. Circ Res 106:463-78
Gitlin, Jonathan M; Homeister, Jonathon W; Bulgrien, Joshua et al. (2009) Disruption of tissue-specific fucosyltransferase VII, an enzyme necessary for selectin ligand synthesis, suppresses atherosclerosis in mice. Am J Pathol 174:343-50
Homeister, Jonathon W; Patterson, Cam (2008) Zinc fingers in the pizza pie aorta. Circ Res 103:687-9