Our long-term objective remains to unravel the genetic complexities of essential hypertension and its complications.
Specific aim (i) will test the hypothesis that blood pressure is controlled by many genetic and environmental factors that individually have only small effects but which in some combinations are detrimental and in others beneficial. Mice having pair-wise combinations of high and low expressing variants at genetic loci (Agtr1a, Npr1, and Pparg) in three different physiological systems will be generated. Telemetric blood pressure monitoring and quantitative RT-PCR will determine the effects on these mice of dietary salt and fat, and of relevant drug treatments, and how homeostatic compensations in their heart, kidneys, adrenals, liver and adipose tissues are affected.
Specific aim (ii) will test the hypothesis that the renin gene outside the kidney is important in blood pressure maintenance. Ren1c-/- mice (which cannot produce renin anywhere), and mice with renin transgenes, RenTgs (which produce renin at different constant levels only in the liver) will be mated, and their Ren1c-/-RenTg progeny will be used to determine whether extra-renal renin can regulate blood pressure. We will transplant non-renin-producing kidneys from Ren1c-/-RenTg mice into wildtype mice to determine whether the Ren1c gene in extra-renal tissues, but not in the kidney, can control blood pressure.
Specific aim (iii) will test the hypothesis that, during hypertensive cardiac hypertrophy, myocytes assume one of two states: hypertrophic but not expressing fetal genes, or hypertrophic and expressing fetal genes. We will induce and reverse hypertension in mice expressing fluorescent indicators of hypertrophy-responsive genes, and assess expression of the indicator and other genes in individual cells to determine whether genes switch concordantly or randomly in individual cells, and whether switched cells can resume their former state. Together these several studies should contribute to a better understanding of how genetic factors affect blood pressure, its homeostasis, and the complications of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049277-19
Application #
7846881
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Thrasher, Terry N
Project Start
1992-09-30
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
19
Fiscal Year
2010
Total Cost
$713,459
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Lawrence, Marlon G; Altenburg, Michael K; Sanford, Ryan et al. (2017) Permeation of macromolecules into the renal glomerular basement membrane and capture by the tubules. Proc Natl Acad Sci U S A 114:2958-2963
Williams, Pete A; Harder, Jeffrey M; Foxworth, Nicole E et al. (2017) Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355:756-760
Willett, Julian Ds; Lawrence, Marlon G; Wilder, Jennifer C et al. (2017) A tetraethylene glycol coat gives gold nanoparticles long in vivo half-lives with minimal increase in size. Int J Nanomedicine 12:2581-2592
Chang, Albert S; Hathaway, Catherine K; Smithies, Oliver et al. (2016) Transforming growth factor-?1 and diabetic nephropathy. Am J Physiol Renal Physiol 310:F689-F696
Chang, Albert S; Grant, Ruriko; Tomita, Hirofumi et al. (2016) Prolactin alters blood pressure by modulating the activity of endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 113:12538-12543
Lawrence, Marlon; Testen, Anze; Koklic, Tilen et al. (2016) A Simple Method for the Size Controlled Synthesis of Stable Oligomeric Clusters of Gold Nanoparticles under Ambient Conditions. J Vis Exp :e53388
Hathaway, Catherine K; Chang, Albert S; Grant, Ruriko et al. (2016) High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy. Proc Natl Acad Sci U S A 113:2218-22
Li, Feng; Fushima, Tomofumi; Oyanagi, Gen et al. (2016) Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia. Proc Natl Acad Sci U S A 113:13450-13455
Smithies, Oliver; Coffman, Tom (2015) A conversation with Oliver Smithies. Annu Rev Physiol 77:1-11
Hathaway, Catherine K; Gasim, Adil M H; Grant, Ruriko et al. (2015) Low TGF?1 expression prevents and high expression exacerbates diabetic nephropathy in mice. Proc Natl Acad Sci U S A 112:5815-20

Showing the most recent 10 out of 120 publications