The evolving understanding of mechanisms contributing to the development of atherosclerosis and neointima formation following vascular injury has identified members of the nuclear hormone receptor superfamily as key transcriptional regulators of gene expression programs controlling inflammation and proliferation. Although much attention has focused on the role of the peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) subfamilies, the nuclear receptor superfamily comprises a large number of so-called orphan nuclear receptors, whose target genes and physiological functions are unknown and remain to be discovered. The neuron-derived orphan receptor-1 (Nor-1) is a constitutively-active transcription factor belonging to the nuclear hormone receptor superfamily. Our Preliminary Data identified Nor-1 expression in human atherosclerotic lesions and in the developing neointima following vascular injury. In response to growth factor stimulation, vascular smooth muscle cells (SMC) rapidly express Nor-1 characterizing this nuclear receptor as an early response gene. Experiments using SMC isolated from Nor-1 deficient mice further reveal that Nor-1 expression is required for SMC proliferation, cell cycle progression, and telomerase activity. Based on these findings, the central hypothesis of this proposal is that Nor-1 functions as a transcriptional regulator of SMC proliferation and thereby contributes to the development of atherosclerosis and neointima formation following vascular injury. To test this hypothesis, we propose the following aims:
Specific Aim 1 : To determine the transcriptional regulation of Nor-1 expression in SMC.
Specific Aim 2 : To determine the molecular mechanisms by which Nor-1 regulates SMC proliferation.
Specific Aim 3 : To determine the contribution of Nor-1 to the development of atherosclerosis by cross- breeding Nor-1 deficient mice to atherosclerosis-susceptible apoE-deficient mice.
Specific Aim 4 : To determine the contribution of Nor-1 to neointima formation using a model of guide-wire induced femoral artery injury in Nor-1 deficient mice. Ultimately, these experiments may characterize a novel transcriptional pathway regulating SMC proliferation in vascular disease and identify suppression of the nuclear receptor Nor-1 as a previously unrecognized target for the treatment of cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084611-04
Application #
7617907
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$355,629
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Qing, Hua; Jones, Karrie L; Heywood, Elizabeth B et al. (2017) Deletion of the NR4A nuclear receptor NOR1 in hematopoietic stem cells reduces inflammation but not abdominal aortic aneurysm formation. BMC Cardiovasc Disord 17:271
Zhao, Yue; Nomiyama, Takashi; Findeisen, Hannes M et al. (2014) Epigenetic regulation of the NR4A orphan nuclear receptor NOR1 by histone acetylation. FEBS Lett 588:4825-30
Qing, Hua; Liu, Yi; Zhao, Yue et al. (2014) Deficiency of the NR4A orphan nuclear receptor NOR1 in hematopoietic stem cells accelerates atherosclerosis. Stem Cells 32:2419-29
Findeisen, Hannes M; Gizard, Florence; Zhao, Yue et al. (2011) Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition. Arterioscler Thromb Vasc Biol 31:851-60
Gizard, Florence; Zhao, Yue; Findeisen, Hannes M et al. (2011) Transcriptional regulation of S phase kinase-associated protein 2 by NR4A orphan nuclear receptor NOR1 in vascular smooth muscle cells. J Biol Chem 286:35485-93
Zhao, Yue; Bruemmer, Dennis (2010) NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler Thromb Vasc Biol 30:1535-41
Zhao, Yue; Howatt, Deborah A; Gizard, Florence et al. (2010) Deficiency of the NR4A orphan nuclear receptor NOR1 decreases monocyte adhesion and atherosclerosis. Circ Res 107:501-11
Nomiyama, Takashi; Zhao, Yue; Gizard, Florence et al. (2009) Deficiency of the NR4A neuron-derived orphan receptor-1 attenuates neointima formation after vascular injury. Circulation 119:577-86
Zhao, Yue; Bruemmer, Dennis (2009) NR4A Orphan Nuclear Receptors in Cardiovascular Biology. Drug Discov Today Dis Mech 6:e43-e48
Gizard, Florence; Nomiyama, Takashi; Zhao, Yue et al. (2008) The PPARalpha/p16INK4a pathway inhibits vascular smooth muscle cell proliferation by repressing cell cycle-dependent telomerase activation. Circ Res 103:1155-63

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