The Yale Specialized Center of Research in Hypertension focuses on identification of the inherited abnormalities that contribute to high blood pressure and its consequences. To date, we have identified mutations in 4 genes that raise blood pressure, 8 genes that lower blood pressure, linkage for two more Mendelian hypertensive disease, and linkage for blood pressure in the general population. These findings have demonstrated the key role of renal salt homeostasis in determination of blood pressure variation in humans, and have begun to identify molecular mechanisms underlying relationships between blood pressure and bone density. In the current proposal, we propose a series of investigations that will extend these studies. Taking genes in which we have shown mutations alter blood pressure, we examine the impact of variants in these genes on blood pressure and related phenotypes in the Framingham Heart Study. We also search for a gene accounting for a substantial fraction of blood pressure variance in this population, and search for genes contributing to a common complication of hypertension, end stage renal disease. We continue our identification of Mendelian traits that affect blood pressure, and pursue the clinical consequences of these mutations. Finally, since virtually all known causes of hypertension act via a common pathway of increased activity of the amiloride-sensitive epithelial sodium channel, we investigate the signaling pathway that regulates the activity of this channel. These studies will continue to provide key information regarding the causes and consequences of hypertension in humans that have clinical and therapeutic implications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL055007-08
Application #
6628988
Study Section
Special Emphasis Panel (ZHL1-CSR-E (S1))
Program Officer
Lin, Michael
Project Start
1996-02-01
Project End
2006-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
8
Fiscal Year
2003
Total Cost
$1,921,605
Indirect Cost
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zhang, Junhui; Geller, David S (2008) Helix 3-helix 5 interactions in steroid hormone receptor function. J Steroid Biochem Mol Biol 109:279-85
Mani, Arya; Radhakrishnan, Jayaram; Wang, He et al. (2007) LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 315:1278-82
Alvarez de la Rosa, Diego; Gimenez, Ignacio; Forbush, Biff et al. (2006) SGK1 activates Na+-K+-ATPase in amphibian renal epithelial cells. Am J Physiol Cell Physiol 290:C492-8
Zhang, Junhui; Tsai, Francis T F; Geller, David S (2006) Differential interaction of RU486 with the progesterone and glucocorticoid receptors. J Mol Endocrinol 37:163-73
Zhang, Junhui; Simisky, Jessica; Tsai, Francis T F et al. (2005) A critical role of helix 3-helix 5 interaction in steroid hormone receptor function. Proc Natl Acad Sci U S A 102:2707-12
Geller, David S (2005) Mineralocorticoid resistance. Clin Endocrinol (Oxf) 62:513-20
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Coric, Tatjana; Hernandez, Nelmary; Alvarez de la Rosa, Diego et al. (2004) Expression of ENaC and serum- and glucocorticoid-induced kinase 1 in the rat intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 286:G663-70
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Francis, Jean; Zhang, Junhui; Farhi, Anita et al. (2004) A novel SGLT2 mutation in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant 19:2893-5

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