This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The demonstration of functional polymorphisms that result in increased receptor density may have direct disease-causing consequences. AbdAlla et al. recently described heterodimerization of B2 receptor and the angiotensin II type 1 (AT1) receptors as a mechanism underlying preeclampsia, a disorder of pregnancy characterized by hypertension, edema, and proteinuria.1,2 The density of heterodimeric receptors was significantly greater in the preeclamptic women compared to normotensive pregnant women and resulted in greater angiotensin II sensitivity, driven not by levels of angiotensin II or its receptor, but by an increased number of B2 receptors. 1,2 The occurrence or significance of heterodimerization in other hypertensive disorders is not known. Therefore, we hypothesize that B2 receptor polymorphisms will alter the density of heterodimerization between B2 receptor and the AT1 receptors. To test this hypothesis, we will determine and compare the density of heterodimerization in platelets obtained from normotensive and hypertensive African Americans and Caucasians. We have demonstrated differential basal gene expression among polymorphisms occurring in 5' promoter/exon1 using a luciferase reporter gene system. In cultured human fibroblasts and other cultured cells, stimulation of cAMP has been shown to result in increased B2 receptor transcription, receptor density, and bradykinin-induced prostaglandin production. Taken together, we hypothesize that B2 receptor polymorphisms will result in differential basal and stimulated receptor density of B2 receptor, which will result in differential bradykinin-induced prostaglandin production. To test this hypothesis, we will perform binding studies in human fibroblasts to determine B2 receptor density among the alleles of the 5' promoter/exon1 haplotypes. We will also compare the production of prostaglandin E2 in response to B2 receptor activation by bradykinin among alleles. Thus, the central hypothesis of this proposal is that B2 receptor polymorphisms result in altered receptor regulation and act as susceptibility factors for vascular pathology. The studies in this proposal will characterize function of genetic variation in the B2 receptor and establish its relevance and therapeutic potential to modify bradykinin-dependent vascular pathology.
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