Project description:The crucial roles of miRNAs have been implicated in various pathological processes, including pancreatitis. However, roles of miRNAs in hypertriglyceridemia-associated pancreatitis have not been reported. Pancreatitis tissue from mice with or without hypertriglyceridemia were analyzed for microRNA profiling. Using qPCR verification, we further identified miR-153 as the most upregulated miRNA in mice with hypertriglyceridemia. This work provide potential therapeutic targets for the treatment of hypertriglyceridemia-associated pancreatitis.
Project description:PAS Pedigrees: Identification of novel genetic variants contributing to cardiovascular disease in pedigrees with premature atherosclerosis.
Project description:Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the non-canonical IkB kinases TBK1 and IKKe with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human subjects. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet (WD)-fed Ldlr-/- mice, and protects against atherogenesis. Amlexanox ameliorates dyslipidemia, inflammation and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrates an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuates monocytosis, eosinophilia and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a new therapy for hypercholesterolemia and atherosclerosis.
Project description:Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of SREBP1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the dominant LXR ligand in macrophage foam cells. Here, we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in liver that lead to hypertriglyceridemia.
Project description:<p>The SEA study is a genome-wide association study to identify genetic variants associated with premature atherosclerosis in subjects included in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) repository - a unique NHLBI resource including data, DNA and arterial specimens from over 3000 multi-ethnic subjects 15-34 years of age who died of non-atherosclerotic causes (mostly trauma). All PDAY subjects had post-mortem quantitative assessment of raised atherosclerotic lesions in their aorta and coronary arteries - making this the largest and most carefully phenotyped cohort for premature atherosclerosis in the world. The goal of the current project was to use the quantitative measure of raised atherosclerotic lesions in the PDAY cohort as the target phenotype for a genome-wide association study and to use quantitative measures of subclinical atherosclerosis (coronary calcium and carotid IMT) in the Multi-Ethnic Study of Atherosclerosis (MESA) to confirm or refute candidate loci identified from the PDAY analysis. Identifying genetic factors that predispose individuals to premature atherosclerosis could lead to more effective screening and early treatment of high risk individuals and suggest novel molecular targets for treatment and prevention interventions.</p>
Project description:Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication, and/or DNA repair. We generated a mouse model with a deletion in the helicase domain of the murine WRN homologue that recapitulates most of the WS phenotypes including an abnormal hyaluronic acid excretion, higher reactive oxygen species (ROS) levels, increased genomic instability and cancer incidence resulting in a 10-15% decreased life span expectancy. In addition, WS patients and Wrn mutant mice show hallmarks of a metabolic syndrome including premature visceral obesity, hypertriglyceridemia, insulin-resistant diabetes type 2 and associated cardiovascular diseases. In this study, we compared the expression profile of liver tissues from 3 months old Wrn mutant mice treated with 0.4% vitamin C to untreated 3 months old Wrn mutant mice. Microarray analyses were performed on the liver tissues of 3 months old mice. Four independent biological replicates of this experiment (untreated Wrn mutant mice vs vitamin C treated Wrn mutant mice) were carried out on four replicates of each genotype.
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare and fatal disease with features of premature aging and cardiovascular diseases (atherosclerosis, myocardial infarction, and stroke). The molecular basis underlying premature aging driven cardiovascular diseases remains incompletely understood. Since endothelial dysfunction is involved in the initiation and progression of cardiovascular diseases. We hypothesized that HGPS-causing progerin (a mutant form of lamin A) and farnesylated prelamin A drives endothelial dysfunction and cardiovascular disease. In our study, we performed transcriptomic profiling of ZMPSTE24-/- mouse endothelial cells, hoping to find the missing link between progeria and atherosclerosis. We observed that ZMPSTE24-/- endothelial cells have increased farnesylated prelamin A accumulation, and show nuclear structure abnormality. Analysis of RNA-seq data revealed that multiple endothelial homeostasis-related genes and pathways are altered by ZMPSTE24 deletion. Further studies are needed to characterize the biological functions of ZMPSTE24 in the pathogenesis of progeria-associated atherosclerosis.
Project description:Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication, and/or DNA repair. We generated a mouse model with a deletion in the helicase domain of the murine WRN homologue that recapitulates most of the WS phenotypes including an abnormal hyaluronic acid excretion, higher reactive oxygen species (ROS) levels, increased genomic instability and cancer incidence resulting in a 10-15% decreased life span expectancy. In addition, WS patients and Wrn mutant mice show hallmarks of a metabolic syndrome including premature visceral obesity, hypertriglyceridemia, insulin-resistant diabetes type 2 and associated cardiovascular diseases. In this study, we compared the expression profile of liver tissues from 3 months old Wrn mutant mice treated with 0.4% vitamin C to wild type animals.