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In utero and early life diesel exposure, epigenetic modification and heart failur

子宫内和生命早期柴油暴露、表观遗传修饰和心力衰竭

基本信息

批准号：
8899545
负责人：
MICHAEL T CHIN
金额：
$ 21.75万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899545
关键词：
Acute Adult Affect Age Air Pollution Animals Antibodies Arrhythmia Blood Pressure C57BL/6 Mouse Cardiovascular Diseases Cardiovascular system ChIP-seq Chromatin Chronic Complication DNA DNA Methylation Development Diesel Exhaust Disease EFRAC Echocardiography Epidemiologic Studies Epigenetic Process Euthanasia Exposure to Female Gender Gene Expression Genetic Transcription Health Heart Heart Arrest Heart Diseases Heart Hypertrophy Heart failure Histone Acetylation Human Hypertrophy Incidence Individual Lead Left Ventricular Hypertrophy Life Link Measures Mediating Modification Molecular Profiling Mus Myocardial Myocardial Infarction Myocardial Ischemia Neonatal Operative Surgical Procedures Particulate Pathway interactions Pattern Perinatal Exposure Population Predisposition Pregnancy Process Systems Biology Time Ventricular Function air filter bisulfite sequencing cohort constriction early life exposure genome-wide histone methylation histone modification in utero mRNA Expression male methylation pattern mortality operation pregnant prenatal exposure pressure prevent transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Diesel exposure has been associated with significant exacerbations in heart disease but the underlying mechanisms by which these exacerbations are mediated and the possible effects of in utero and early life exposure are poorly understood. We have found that mice exposed to diesel exhaust in utero and/or early in life develop increased left ventricular hypertrophy and a predisposition to heart failure as adults. Specificall, we have found that male mice exposed to diesel exhaust in utero and/or early in life develop left ventricular hypertrophy compared to those exposed to filtered air, while female mice exposed in utero and postnatally develop decreased ejection fraction. When the male mice undergo aortic banding, they progress more rapidly to heart failure than the filtered air controls. We hypothesize that in utero exposure to diesel exhaust creates epigenetic modifications in the hearts of exposed animals that predispose to myocardial hypertrophy and/or heart failure as adults, in possibly a gender specific fashion. Accordingly, we propose to examine genome wide epigenetic modifications in neonatal and adult mouse hearts after in utero exposure to diesel exhaust. We will also examine how these modifications vary by gender and alter global RNA expression patterns immediately after exposure and after transverse aortic constriction, a potent inducer of cardiac hypertrophy. We predict that diesel exhaust will induce epigenetic changes that alter expression of genes that confer susceptibility to hypertrophy and heart failure.

描述（由申请方提供）：柴油暴露与心脏病显著加重相关，但对这些加重的潜在介导机制以及宫内和生命早期暴露的可能影响知之甚少。我们已经发现，在子宫内和/或生命早期暴露于柴油机废气的小鼠在成年后发生增加的左心室肥大和心力衰竭的易感性。具体而言，我们发现，与暴露于过滤空气的雄性小鼠相比，在子宫内和/或生命早期暴露于柴油机废气的雄性小鼠发生左心室肥大，而在子宫内和出生后暴露于柴油机废气的雌性小鼠发生射血分数降低。当雄性小鼠进行主动脉结扎时，它们比过滤空气对照组更快地发展为心力衰竭。我们假设，在子宫内暴露于柴油机废气中会在暴露动物的心脏中产生表观遗传修饰，这些修饰可能以性别特异性的方式使暴露动物在成年后易患心肌肥大和/或心力衰竭。因此，我们建议检查子宫内暴露于柴油机废气后新生和成年小鼠心脏的全基因组表观遗传修饰。我们还将研究这些修饰如何因性别而异，并在暴露后立即改变全球RNA表达模式，以及在横向主动脉缩窄后改变全球RNA表达模式，横向主动脉缩窄是心脏肥大的有力诱导剂。我们预测，柴油机废气会引起表观遗传变化，改变基因的表达，赋予肥大和心力衰竭的易感性。