Epigenomics of Atherosclerosis

动脉粥样硬化的表观基因组学

• 批准号: 7725759
• 负责人: JESSICA J CONNELLY
• 金额: $ 35.74万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-08 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7725759
• 关键词: Accounting; Aorta; Atherosclerosis; Blood Vessels; Cells; Coculture Techniques; Code; Complex; Cytosine; DNA Methylation; Data; Disease; Disease model; Dissection; Endothelial Cells; Epigenetic Process; Equilibrium; Gene Expression Regulation; Genes; Genetic; Genome; Human; Human body; Intervention; Lead; Lipids; Maps; Methods; Methylation; Modeling; One-Step dentin bonding system; Pathway interactions; Phenotype; Play; Role; Scientist; Smooth Muscle Myocytes; Tissues; Uncertainty; Variant; disease phenotype; disorder risk; epigenomics; novel; public health relevance; research study; tool

DESCRIPTION (provided by applicant): As our understanding of the intricate mechanisms of gene regulation increases, it is apparent that traditional methods of identifying aberrant genetic mechanisms associated with complex disease, such as linkage and association studies, will not be sufficient. Additionally, the traditional paradigm that variants that lead to disease must exist within the coding region of a gene needs to be changed. One step in better modeling of disease risk and understanding disease variants lies in expanding the paradigm of complex disease study to include epigenetic influences that contribute to diseases. We hypothesize that changes in DNA methylation status of genes in endothelial cells (ECs) and smooth muscle cells (SMCs) undergoing phenotypic switching, a hallmark of atherosclerosis formation, could play a role in atherosclerosis initiation and progression. This proposal specifically seeks to create comprehensive maps of the cytosine methylated genome in (1) ECs and SMCs under a disease and (2) non-disease state influenced using a novel and validated human surrogate vascular co-culture model that can recalibrate the EC and SMC phenotype into a healthy or atheroprone phenotype outside the human body and (3) diseased and non-diseased human aorta tissue. We tackle three paradigms to demonstrate how to evaluate cytosine methylation changes, in healthy cells and tissues, in disease cells and tissues, and in early (flow phenotype) and late (lipid and plaque laden tissue) atherosclerosis. In addition, highthroughput sequencing methods and tools will be developed using these data and be made available to all scientists. Public Health Relevance: It is becoming clear that disease models of genetic and epigenetic changes will no doubt account for a majority of the complex disease phenotype. The short range impact of the experiments proposed here will be to uncover another entire layer of potentially heritable gene regulation that will bring us closer to understanding early atherosclerosis and may provide us with candidate pathways for intervention. Our long range impacts will come from the dissection of the normal and disease marks we identify to better understand the cell and its balance between a non-disease and diseased (atherosclerosis) state.

描述（由申请人提供）：随着我们对基因调节的复杂机制的理解增加，很明显，鉴定与复杂疾病相关的异常遗传机制（例如连锁和关联研究）的传统方法将不够。此外，必须改变导致疾病的变体的传统范式必须在基因的编码区域内进行更改。更好地建模疾病风险和理解疾病变异的一步在于扩大复杂疾病研究的范式，包括有助于疾病的表观遗传影响。我们假设在内皮细胞（ECS）和平滑肌细胞（SMC）进行表型转换（动脉粥样硬化形成的标志）中，基因的DNA甲基化状态的变化可能在动脉粥样硬化的起始和进展中起作用。该提案专门旨在在（1）EC和SMC中创建疾病中的胞嘧啶甲基化基因组的综合图，以及（2）非疾病状态使用新颖且经过验证的人类替代的替代性血管培养模型影响，可以将EC和SMC表型重新验证为健康或动脉粥样硬化的人体和不良的人体和（3）。我们解决了三个范式，以演示如何评估健康细胞和组织，疾病细胞和组织以及早期（流动表型）和晚期（脂质和斑块载体组织）动脉粥样硬化中的胞嘧啶甲基化变化。此外，将使用这些数据开发高通量测序方法和工具，并向所有科学家提供。公共卫生相关性：很明显，遗传和表观遗传变化的疾病模型无疑会占复杂疾病表型的大部分。这里提出的实验的短范围影响是揭示另一个潜在的可遗传基因调节层，这将使我们更加了解早期动脉粥样硬化，并可能为我们提供候选途径进行干预。我们的远距离影响将来自我们确定的正常和疾病标记的解剖，以更好地理解细胞及其在非疾病和患病（动脉粥样硬化）状态之间的平衡。