The long term goal of our research is to develop a deep understanding of the genetic factors underlying atherosclerosis, using mice genetically altered by targeting. The upcoming grant period will take advantage of the predictable development of atherosclerosis in our apolipoprotein E-deficient mice to explore how the atherogenic process is affected by mutations in genes other than those directly involved in lipid metabolism. The genes chosen for study in our three specific aims are each individually important for maintaining vascular health and eanh is a likely candidates for altering the vascular response to elevated levels of plasma lipoproteins. In addition, changes in these genes are likely to make current mouse models of atherosclerosis closer to the human condition.
Specific aim 1 : We will generate a genetic absence of ascorbic acid (vitamin C) synthesis in mice, by disrupting the mouse L-gulono-gamma- lactone oxidase gene, which humans lost during the evolution. We will combine this with a genetic lack of apoE to test the importance of this dietary antioxidant in the prevention of atherosclerosis and in stabilizing atherosclerotic plaques.
Specific aim 2 : We will test the importance of monocyte recruitment for early lesion development by generating apoE null mice carrying 0, 1, 2, 3, or 4 copies of the chemokine receptor CCR2 gene, coding for the primary receptor for the chemokine MCP-1 (monocyte chemoattractant protein 1).
Specific aim 3 : We will test the hypothesis that mutations causing elevation in the blood pressures of animals will influence the development, distribution, and the stability of atherosclerotic plaques by combining apoE deficiency with mutations in genes coding for angiotensinogen, endothelial nitric oxide synthase or natriuretic peptide receptor A.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL042630-11
Application #
2901120
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1989-04-01
Project End
2003-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kayashima, Yukako; Makhanova, Natalia; Maeda, Nobuyo (2017) DBA/2J Haplotype on Distal Chromosome 2 Reduces Mertk Expression, Restricts Efferocytosis, and Increases Susceptibility to Atherosclerosis. Arterioscler Thromb Vasc Biol 37:e82-e91
Liu, Ya-Hui; Tsai, Yau-Sheng; Lin, Shih-Chieh et al. (2016) Quantitative PPAR? expression affects the balance between tolerance and immunity. Sci Rep 6:26646
Tai, Haw-Chih; Tsai, Pei-Jane; Chen, Ju-Yi et al. (2016) Peroxisome Proliferator-Activated Receptor ? Level Contributes to Structural Integrity and Component Production of Elastic Fibers in the Aorta. Hypertension 67:1298-308
Kayashima, Yukako; Makhanova, Natalia A; Matsuki, Kota et al. (2015) Identification of aortic arch-specific quantitative trait loci for atherosclerosis by an intercross of DBA/2J and 129S6 apolipoprotein E-deficient mice. PLoS One 10:e0117478
Hiller, Sylvia; DeKroon, Robert; Xu, Longquan et al. (2014) ?-Lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice. Free Radic Biol Med 71:362-7
Kayashima, Yukako; Tomita, Hirofumi; Zhilicheva, Svetlana et al. (2014) Quantitative trait loci affecting atherosclerosis at the aortic root identified in an intercross between DBA2J and 129S6 apolipoprotein E-null mice. PLoS One 9:e88274
Wait, John M S; Tomita, Hirofumi; Burk, Laurel M et al. (2013) Detection of aortic arch calcification in apolipoprotein E-null mice using carbon nanotube-based micro-CT system. J Am Heart Assoc 2:e003358
Johnson, Lance A; Kim, Hyung-Suk; Knudson, Melissa J et al. (2013) Diabetic atherosclerosis in APOE*4 mice: synergy between lipoprotein metabolism and vascular inflammation. J Lipid Res 54:386-96
Wölkart, G; Beretta, M; Wenzl, M V et al. (2013) Tolerance to nitroglycerin through proteasomal down-regulation of aldehyde dehydrogenase-2 in a genetic mouse model of ascorbate deficiency. Br J Pharmacol 168:1868-77
Fox, Raymond G; Magness, Scott; Kujoth, Gregory C et al. (2012) Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption. Am J Physiol Gastrointest Liver Physiol 302:G914-24

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