A central problem in genetics is how substantial shifts in the overall gene expression programs of individual cells are achieved during development and in adult cells when they adapt homeostatically to a disturbance. As a framework against which to investigate this problem, we propose a """"""""two-state"""""""" hypothesis, which we will test in relation to the complex homeostatic shifts in gene expression program that accompany the development and regression of left ventricular cardiac hypertrophy, an important cardiovascular risk factor independent of hypertension. The hypothesis states that adult cells (such as cardiac myocytes) when stressed sufficiently can switch without cell division to an alternative state in which the expression of many genes differ co-ordinately. ? ? Specific aim i) will test whether individual cardiac myocytes switch expression of representative genes coordinately between two states, and whether the degree of hypertrophy is mediated by the proportion of cells in the two states. ? ? Specific aim ii) will increase the stringency of the tests by using a much broader panel of discriminators with several categorically different ways of inducing hypertrophy, and will also test whether the hypertrophic cells replicate the expression pattern of normal cells at an earlier stage of development. ? ? Specific aim iii) will test the hypothesis that the expression programs of cardiac myocytes in the hypertrophic state can under appropriate circumstances switch back to the normal state in animals in vivo, or in tissue culture ex vivo. ? ? Our proposal is, to our knowledge, the first attempt to formalize how complex shifts in gene expression programs are achieved in cells responding to homeostatic challenges, but the value of the proposed experiments does not depend on the correctness of the two-state hypothesis since each specific aim also addresses a gap in current knowledge related to cardiac hypertrophy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071266-33
Application #
6784150
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Evans, Frank
Project Start
1988-09-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
33
Fiscal Year
2004
Total Cost
$362,706
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
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
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
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
Matsuki, Kota; Hathaway, Catherine K; Chang, Albert S et al. (2015) Transforming growth factor beta1 and aldosterone. Curr Opin Nephrol Hypertens 24:139-44
Hathaway, Catherine K; Grant, Ruriko; Hagaman, John R et al. (2015) Endothelin-1 critically influences cardiac function via superoxide-MMP9 cascade. Proc Natl Acad Sci U S A 112:5141-6
Kakoki, Masao; Pochynyuk, Oleh M; Hathaway, Catherine M et al. (2013) Primary aldosteronism and impaired natriuresis in mice underexpressing TGF?1. Proc Natl Acad Sci U S A 110:5600-5
Kakoki, Masao; Smithies, Oliver (2009) The kallikrein-kinin system in health and in diseases of the kidney. Kidney Int 75:1019-30
Pandya, Kumar; Porter, Kristine; Rockman, Howard A et al. (2009) Decreased beta-adrenergic responsiveness following hypertrophy occurs only in cardiomyocytes that also re-express beta-myosin heavy chain. Eur J Heart Fail 11:648-52
Pandya, Kumar; Cowhig, John; Brackhan, Joe et al. (2008) Discordant on/off switching of gene expression in myocytes during cardiac hypertrophy in vivo. Proc Natl Acad Sci U S A 105:13063-8
Takahashi, Nobuyuki; Li, Feng; Hua, Kunjie et al. (2007) Increased energy expenditure, dietary fat wasting, and resistance to diet-induced obesity in mice lacking renin. Cell Metab 6:506-12

Showing the most recent 10 out of 23 publications