Grant: $543,710 - National Institutes of Health - Aug. 31, 2009
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Award Description: Elevations in the circulating level of C-reactive protein (CRP) are a strong predictor of the development of hypertension and insulin resistance. The proposed research program will determine how CRP and its cell surface receptors cause hypertension and insulin resistance.
Project Description: The circulating level of C-reactive protein (CRP) is a strong predictor of endothelial dysfunction and hypertension in humans. In CRP-transgenic mice(TG-CRP), we showed that CRP attenuates endothelial NO synthase (eNOS) expression leading to endothelial dysfunction and hypertension. Cell culture studies indicate that CRP also impairs insulin-induced eNOS activation, and we have discovered that TG-CRP mice are insulin resistant. Further recent work shows that the hypertension in TG-CRP mice is mediated by the inhibitory IgG Fcgamma receptor (FcR) FcRIIB. We now also have direct evidence of endothelial cell expression of FcRIIB. The OVERALL PURPOSE of the project is to test the hypothesis that CRP actions via endothelial FcRIIB cause both hypertension and insulin resistance. We are generating floxed FcRIIB mice (FcRIIBflox/flox), which will be crossed with mice expressing tamoxifen-inducible Cre-recombinase under the regulation of the vascular endothelial cadherin promoter (VECad-Cre-ERT2) to selectively delete receptor expression in endothelium. FcRIIBflox/flox;VECad-Cre-ERT2 mice will be crossed with TG-CRP, and following tamoxifen treatment, chronic blood pressure (BP) measurements will be done by radiotelemetry. In the past quarter we have been screening mouse lines to identify those expressing the floxed FcRIIB allele. We have also been breeding VECad-Cre-ERT2 mice in preparation for crosses with Rosa26 Reporter mice for studies to optimize the tamoxifen treatment for endothelial cell-specific Cre expression. In addition, we have been proceeding with the studies of CRP and insulin resistance by evaluating the glucose infusion rate during hyperinsulinemic-euglycemic clamps and skeletal muscle glucose uptake in control and TG-CRP mice. This recent work is integral to our proposed research program,which will provide important new understanding of the mechanisms by which CRP has a direct negative impact on both vascular and metabolic health.
Jobs Summary: No jobs were created, only retained. (Total jobs reported: 3)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 31, 2009. Help expand these official descriptions using the wiki below.