Investigating the Role of Epigenetic Changes in Early Development and Prevention of Cardiovascular Inflammation

项目总结 在美国，心血管疾病(CVD)和2型糖尿病患者每37秒就有一人死亡 糖尿病(T2 DM)患者在心肌梗死后的死亡率要高出2倍。2型糖尿病的主要病因 发病率和死亡率为脑血管病。T2 DM的遗传危险因素和生物标志物已被确定，但 准确预测心血管并发症。一种新兴的2型糖尿病心血管疾病早期预测方法 是表观遗传学。表观遗传变化是对基因组的修饰，它调节基因转录，而不是 实际上改变了潜在的核苷酸序列。内皮细胞(ECs)，排列在血液内部 血管，在T2 DM中变得功能失调，是CVD进展的第一步。ECS保持长期 即使在达到正常血糖水平后，促炎基因的表达也是如此，这表明 表观遗传变化可能是导致心血管疾病的基因表达持久变化的原因。它是 然而，尚不清楚表观遗传学变化在多大程度上介导了早期心脏内皮细胞功能障碍 以及这些变化是否可以通过锻炼等生活方式干预来挽救。短期内 该项目的目标是确定高血糖对表观遗传修饰的影响(通过 染色质可及性)，以及运动干预是如何改变这些的。 翻译小鼠模型。长期目标是帮助开发早期有效的预测、预防和 2型糖尿病患者心血管并发症的处理。我假设高血糖会导致 炎症途径基因中染色质的差异可及性将被并发预防 有氧运动。我将通过两个具体目标来验证这一假设：1.确定高血糖的影响 胰岛素抵抗对心肌内皮细胞表观遗传学的影响。我会用一个平移鼠标 模型，以实现饮食干预和分离心脏内皮细胞 细胞。2.测试有氧运动干预是否能防止高血糖引起的表观遗传学改变 心脏内皮细胞。我将测试四组随机分配的小鼠：对照饮食(CD)，CD运动， 高脂饮食(HFD)，HFD运动。这个项目具有重大意义和创新性，因为它研究了一个长期的- 用一种新的表观遗传学分析方法确定一种极端流行疾病的死亡原因。这 项目符合申请者的长期研究目标，即使用翻译科学模型来改进 慢性代谢病患者心血管并发症的认识、预防和治疗 疾病。这项研究将建立高血糖和胰岛素抵抗的早期影响 心脏内皮细胞的表观遗传学变化以及是否可以通过运动缓解这些变化， 为心血管并发症的早期有效识别和治疗奠定基础 T2 DM组。拟议的研究与NINR战略计划的三个领域--健康促进和 预防疾病，提高生活质量，创新。

PROJECT SUMMARY Cardiovascular disease (CVD) kills one person every 37 seconds in the U.S. and those with type 2 diabetes mellitus (T2DM) have a 2-fold higher mortality following a myocardial infarction. The principal cause of T2DM morbidity and mortality is CVD. Genetic risk factors and biomarkers for T2DM have been identified but neither accurately predicts cardiovascular complications. An emerging, novel early prediction method of CVD in T2DM is epigenetics. Epigenetic changes are modifications to the genome that regulate gene transcription without actually changing the underlying nucleotide sequence. Endothelial cells (ECs), which line the interior of blood vessels, become dysfunctional in T2DM and are the first step in CVD progression. ECs maintain long-term expression of pro-inflammatory genes even after normal glucose levels have been attained, suggesting epigenetic changes might be responsible for enduring changes in gene expression that contribute to CVD. It is unknown, however, the extent to which epigenetic changes mediate early cardiac endothelial cell dysfunction in T2DM and whether these changes can be rescued with lifestyle interventions like exercise. The short-term goal of this project is to determine the effect of hyperglycemia on epigenetic modifications (measured via chromatin accessibility) in cardiac endothelial cells and how these are modified by an exercise intervention in a translational mouse model. The long-term goal is to help develop early effective prediction, prevention, and management of cardiovascular complications in patients with T2DM. I hypothesize hyperglycemia will cause differential chromatin accessibility in inflammatory pathway genes that will be prevented by concurrent aerobic exercise. I will test this hypothesis using two specific aims: 1. Determine the effect of hyperglycemia and insulin resistance on epigenetic changes in cardiac endothelial cells. I will use a translational mouse model, which is readily available in our lab, to implement a diet intervention and isolate cardiac endothelial cells. 2. Test whether an aerobic exercise intervention prevents hyperglycemia-induced epigenetic changes in cardiac endothelial cells. I will test four randomly assigned groups of mice: control diet (CD), CD + exercise, high fat diet (HFD), HFD + exercise. This project is significant and innovative because it investigates a long- standing cause of death in an extremely prevalent disease using a novel epigenetic analysis approach. This project fits within the applicant’s long-term research goals of using translational science models to improve understanding, prevention, and treatment of cardiovascular complications in patients with chronic metabolic diseases. This research will establish the early effects of hyperglycemia and insulin resistance on epigenetic changes in cardiac endothelial cells and whether they can be mitigated through exercise, setting the groundwork for effective early identification and treatment of cardiovascular complications in T2DM. The proposed study is aligned with three of the NINR Strategic Plan areas – health promotion and disease prevention, advancing the quality of life, and innovation.