Like many other quantitative traits, arterial blood pressure is a phenotype that is determined by the interaction of multiple genetic and environmental factors. Although some progress has been made in elucidating a few of the environmental factors that contribute to hypertension, less progress has been made in identifying the genes that play a role in this disorder. Choosing potential candidate genes involved in regulating blood pressure has been aided by data from extensive physiological experimentation. The control of arterial blood pressure depends on both extracellular fluid volume and vascular resistance. The regulation of the former parameter is accomplished via short term mechanisms such as the renin angiotensin- aldosterone system and athe atrial natriuretic peptide system, and over the long term, by pressure diuresis/natriuresis. This is carried out in both short and long term control mechanisms by tahe modulation of sodium and water reabsorption along the nephron. The sodium transporters, which are the molecular effectors of this reabsorption process are therefore likely, if dysregulated by mutation, to manifest a phenotype of altered blood pressure. The objective of this component of the POEMB will be to test the genes encoding the major sodium transporters for linkage ta the phenotype of high blood pressure. We will isolate highly polymorphic PCR markers at the following loci: The apical Na/H exchanger of the proximal tubule (NHE3), the apical Na,K,2C1 cotransporter of the thick ascending limb of henle, the apical NaC1 cotransporter of the distal convoluted tubule, the alpha, beta and gamma subunits of the apical Na+ channel of the collecting duct, the basolateral Na/H exchangers (NHE2 and NHE4), the basolateral Na,K,2C1 cotransporter, the alpha1 and beta1 subunits of the basolateral Na,K,ATPase. Polymorphic DNA markers at these loci will be tested for linkage to the phenotype of essential hypertension by using the """"""""affected sib pair"""""""" method in large (approximately 150 sibships), well characterized African American populations of hypertensive and normotensive individuals of which 70 sibships have already been collected in collaboration with Dr. Max Reif (Hypertension Clinic, university of Cincinnati). Other, well characterized hypertensive and control populations of European ancestry will also be tested for linkage to these markers in collaboration with Drs. Jean Marc Lalouel (approximately 200 affected sib pairs from Utah) and pierre Corvol (approximately 400 affected sib pairs from France). We anticipate that the genetic markers developed in this component will become widely used. Moreover, athe availability of such African American populations might provide insights into the known epidemiological differences in how this disorder effects individuals of European or African ancestry.
| Sadayappan, Sakthivel; Finley, Natosha; Howarth, Jack W et al. (2008) Role of the acidic N'region of cardiac troponin I in regulating myocardial function. FASEB J 22:1246-57 |
| Pattison, James Scott; Waggoner, Jason R; James, Jeanne et al. (2008) Phospholamban overexpression in transgenic rabbits. Transgenic Res 17:157-70 |
| Kalinichenko, Vladimir V; Gusarova, Galina A; Kim, Il-Man et al. (2004) Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development. Am J Physiol Lung Cell Mol Physiol 286:L521-30 |
| Small, Kersten M; McGraw, Dennis W; Liggett, Stephen B (2003) Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol 43:381-411 |
| Sanbe, Atsushi; Gulick, James; Hanks, Mark C et al. (2003) Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. Circ Res 92:609-16 |
| Liggett, Stephen B (2003) Polymorphisms of adrenergic receptors: variations on a theme. Assay Drug Dev Technol 1:317-26 |
| Golovina, Vera A; Song, Hong; James, Paul F et al. (2003) Na+ pump alpha 2-subunit expression modulates Ca2+ signaling. Am J Physiol Cell Physiol 284:C475-86 |
| Kalinichenko, Vladimir V; Zhou, Yan; Shin, Brian et al. (2002) Wild-type levels of the mouse Forkhead Box f1 gene are essential for lung repair. Am J Physiol Lung Cell Mol Physiol 282:L1253-65 |
| Whitsett, Jeffrey A; Clark, Jean C; Picard, Lara et al. (2002) Fibroblast growth factor 18 influences proximal programming during lung morphogenesis. J Biol Chem 277:22743-9 |
| Lim, Lorena; Kalinichenko, Vladimir V; Whitsett, Jeffrey A et al. (2002) Fusion of lung lobes and vessels in mouse embryos heterozygous for the forkhead box f1 targeted allele. Am J Physiol Lung Cell Mol Physiol 282:L1012-22 |
Showing the most recent 10 out of 257 publications
