Transcriptional and Epigenetic regulation of P66shc: relevance to endothelial fun

描述(申请人提供)：全球和地区性表观遗传学变化与越来越多的人类疾病有关，包括各种癌症、风湿性和自身免疫性疾病以及先天性和遗传性疾病。表观遗传学也迅速引起了心血管生物学的关注。特定基因的局部表观遗传学变化与动脉粥样硬化的年龄相关性发展和高血压的胎儿程序化有关。这一应用是基于这样一种假设，即p66shc基因的表观遗传学变化有助于促进血管氧化应激和减少血管一氧化氮，导致内皮依赖性血管功能障碍的发病。它将描述控制内皮细胞p66shc表达的转录机制(S)，确定表观遗传变化在调节这一表达中的作用，并探索这些转录和表观遗传机制在内皮依赖性血管舒缩张力受损动物模型中的生理相关性。通过研究表观遗传学和转录如何协同调节内皮和血管壁中p66shc的表达，并促进p66shc介导的内皮依赖性血管紧张性功能障碍，这一应用有望为理解特定基因及其与环境的相互作用在血管疾病的发病机制中发挥作用迈出重要的新一步。与公共卫生相关：除了基因DNA序列的改变外，DNA表观遗传改变的修改现在被认为是导致越来越多的人类疾病，如癌症和自身免疫性疾病。我们认为，导致血管功能失调的基因p66shc的表观遗传学变化在决定p66shc是否在血管中表达并因此导致血管功能障碍方面发挥了重要作用。

DESCRIPTION (provided by applicant): Global and regional epigenetic changes have been implicated in a growing number of human diseases including various cancers, rheumatic and autoimmune diseases, as well as congenital and hereditary disorders. Epigenetics is also rapidly gaining attention is cardiovascular biology. Focal epigenetic changes in specific genes have been implicated in the age-dependent development of atherosclerosis and in the fetal programming of hypertension. This application is based on the hypothesis that epigenetic changes in the gene for p66shc, a protein that promotes vascular oxidative stress and decreases vascular nitric oxide, contribute to the pathogenesis of endothelium-dependent vascular dysfunction. It will characterize the transcriptional mechanisms(s) controlling p66shc expression in the endothelium, determine the role of epigenetic changes in modulating this expression, and explore the physiological relevance of these transcriptional and epigenetic mechanisms in animal models of impaired endothelium-dependent vasomotor tone. By studying how epigenetics and transcription, in concert, regulate p66shc expression in the endothelium and vascular wall, and contribute to p66shc-mediated endothelium-dependent dysfunction of vascular tone, this application promises to take an important new step toward understanding how specific genes, and their interaction with the environment, play a part in the pathogenesis of vascular disorders. PUBLIC HEALTH RELEVANCE: In addition to alterations in gene DNA sequences, modifications of DNA epigenetic changes are now thought to contribute to a growing number of human diseases such as cancers and autoimmune disorders. We propose that epigenetic changes in p66shc, a gene that contributes to dysregulation of blood vessel function, play an important part in determining whether p66shc is expressed in blood vessels, and therefore contributes to dysfunction of such vessels.