The overall objective of this project is to develop a deeper understanding of the genetic variants underlying dyslipidemia and atherosclerosis. We will use mouse genetics as a tool to gain insight into human atherogenesis where the effects of the common human polymorphic variants are small at the level of individuals but large at the population level. For example, increased plasma low-density lipoproteins (LDL) and an increased risk of developing atherosclerosis are associated in humans with the three common alleles of APOE in the order of APOE*4 >APOE*3 >APOE*2. Toward solving the mechanisms underlying this association, we have generated mice expressing human apoE2, E3 or E4 in place of mouse apoE. These mice recapitulate the human results, but only when they also express high levels of the human LDL receptor (LDLR). Thus these humanized mice have revealed an important interplay between the apoE isoforms and LDLR levels in a manner previously not suspected. Because the apoE polymorphism is so common and its associated risks are so definite, our first two specific aims will use the humanized mice to better define the differential contributions of the apoE-isoforms to the risk of developing atherosclerosis and the metabolic syndrome (an aggregation of obesity, dyslipidemia, insulin resistance, and hypertension).
Specific Aim 1 will test the hypothesis that interactions between the apoE isoforms and LDLR play an important role in adipocyte function and thence in atherogenesis using experiments in cultured preadipocytes and in vivo experiments in a mouse genetic model of obesity.
Specific Aim 2 will test the hypothesis that the human variants of apoE interact with variants of peroxisome proliferator-activated receptor gamma (PPAR?) in determining the functionality of adipocytes and thence the development of the metabolic syndrome. Strain 129S6 and C57BL/6J mice that are Apoe-/- develop plaques preferentially at different sites (the aortic root and the aortic arches), at different rates, and with differences in the effects of gender. They also have strain-specific differences in the geometry of their aortic arches.
Our Specific Aim 3 will explore a new direction of atherosclerosis studies-namely the identification of genetic factors influencing the locations of plaque development. We will use SNP analysis to map strain-specific genetic factors that influence the site preference and gender effects, and test whether strain differences in arterial geometry play a role in the location of plaques. Identifying genetic loci that affect these variables should provide new and important tools for better identifying individuals at high risk of atherosclerosis before the disease has developed.
Cardiovascular diseases resulting from clogging of the arteries (atherosclerosis) account for a large proportion of sickness and deaths in advanced societies. The risk of developing atherosclerosis in individuals is determined by genetic and life-style factors. Using mouse genetics as a tool, we aim to determine how some common human genetic differences affect atherosclerosis and how the genetic effects are influenced by being overweight and by other common gene variants.
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|Govindapillai, Arun; Hotchkiss, Adam; Baguma-Nibasheka, Mark et al. (2018) Characterizing the role of atrial natriuretic peptide signaling in the development of embryonic ventricular conduction system. Sci Rep 8:6939|
|Engstrom, Anna K; Snyder, Jessica M; Maeda, Nobuyo et al. (2017) Correction to: Gene-environment interaction between lead and Apolipoprotein E4 causes cognitive behavior deficits in mice. Mol Neurodegener 12:81|
|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|
|Makhanova, Natalia; Morgan, Andrew P; Kayashima, Yukako et al. (2017) Genetic architecture of atherosclerosis dissected by QTL analyses in three F2 intercrosses of apolipoprotein E-null mice on C57BL6/J, DBA/2J and 129S6/SvEvTac backgrounds. PLoS One 12:e0182882|
|Engstrom, Anna K; Snyder, Jessica M; Maeda, Nobuyo et al. (2017) Gene-environment interaction between lead and Apolipoprotein E4 causes cognitive behavior deficits in mice. Mol Neurodegener 12:14|
|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|
|Arbones-Mainar, J M; Johnson, L A; Torres-Perez, E et al. (2016) Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4. Int J Obes (Lond) 40:1574-1581|
|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|
|Hiller, Sylvia; DeKroon, Robert; Hamlett, Eric D et al. (2016) Alpha-lipoic acid supplementation protects enzymes from damage by nitrosative and oxidative stress. Biochim Biophys Acta 1860:36-45|
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