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Single nucleotide polymorphisms in the human prostacyclin gene: implications for cardiovascular disease and genetic mutagenesis.

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Call No.	QP752.P69 A74 2008
Author	Arehart, Eric.
Title	Single nucleotide polymorphisms in the human prostacyclin gene: implications for cardiovascular disease and genetic mutagenesis.
Date	2008
Abstract	Prostacyclin (PGI 2 ) is a major product of COX-2 catalyzed metabolism of arachidonic acid in the endothelium and has been shown to be atheroprotective. PGI 2 signals though its G-coupled protein receptor (GPCR) the human Prostacyclin receptor (hIP) leading to the downstream production of cAMP thereby mediating a number of cellular pathways. The prostacyclin receptor knockout mice exhibit increased atherosclerosis, enhanced thrombosis, and enhanced proliferative response to carotid vascular injury with increased intima to media ratios 1-3. Single nucleotide polymorphisms (SNPs) constitute greater than 80% of our genetic diversity and are known to play a role in the pathogenesis of disease and individual response to medical therapy. This thesis sets forth to: (1) determine the clinical significance of certain SNPs in the hIP gene and their association with cardiovascular disease (CVD), (2) Determine the relationship between hIP expression in human platelets with CVD severity, and (3) elucidate certain nucleotide motifs in the human genome that may contribute to SNP genesis. Using site-directed mutagenesis, this thesis identifies the effects of novel hIP polymorphisms on expression, binding and activation. Here we show that specific alterations in hIP structure can lead to alterations in protein function. In particular such work has been useful in identifying protein domains essential for proper binding and activation. Using saturation binding on human whole blood collected from our patients recruited from Dartmouth-Hitchcock Medical Center (CPHS approval #14888), this thesis identifies a novel association between increased hIP expression levels and cardiovascular disease. Additionally, using our cAMP activation assay, this thesis identifies cAMP levels in platelets as a potential molecular switch with regard to hIP expression. Using computational methods, this thesis demonstrates the existence of a conserved motif in the flanking regions of documented SNP sites. This motif has been shown to demonstrate a conserved motif and that this motif is expanded in certain SNP subtypes.
Description	xx, 188 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Hwa, John, DeLeo, Joyce, Moore, Jason, Lowrey, Christopher
Subject	Prostacyclin -- Receptors. Chromosome polymorphism. Cardiovascular system -- Diseases -- Genetic aspects. Polymorphism.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.206

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	SINGLE NUCLEOTIDE POLYMORPHISMS IN THE HUMAN PROSTACYCLIN GENE: IMPLICATIONS FOR CARDIOVASCULAR DISEASE AND GENETIC MUTAGENESIS A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Eric Arehart DARTMOUTH COLLEGE Hanover, New Hampshire May 19, 2008 Thesis Committee __________________________________ (Thesis Advisor) John Hwa, M.D./Ph.D. _________________________________ Joyce DeLeo, Ph.D _________________________________ Jason Moore, Ph.D. _________________________________ Christopher Lowrey, M.D. _____________________________ Charles K. Barlowe, Ph.D. Dean of Graduate Studies

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