高血压血管重塑中血管保护分子CREG基因表达的上游调控机制研究

项目名称： 高血压血管重塑中血管保护分子CREG基因表达的上游调控机制研究

项目编号： No.81500329

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张权宇

作者单位： 中国人民解放军北部战区总医院

项目金额： 18万元

中文摘要： 从血管稳态调控角度，寻找对抗血管重塑的关键调控分子和信号通路，成为高血压病因学和治疗学领域新的、重要的研究方向。E1A激活基因阻遏子（CREG）是一个新发现的具有血管稳态调节作用的内源性分子，我们发现在血管紧张素II（Ang II）诱导的小鼠高血压模型中，主动脉中CREG基因表达下调早于血管重塑发生，并且CREG+/-小鼠的血管重塑程度较CREG+/+小鼠更为显著，我们推测：CREG是血管重塑中的关键调控因子，其表达降低促进高血压发生。本研究拟建立Ang II诱导的继发性小鼠高血压模型，通过重组人CREG蛋白外源性干预明确其在高血压血管重塑中的作用，并进一步从转录因子调控角度探讨CREG基因表达下调的分子机制。通过本研究的完成，尝试阐明高血压血管重塑中CREG基因表达抑制的上游调控机制，为临床高血压及血管稳态失衡引起血管性疾病的防治研究提供重要思路和新的治疗靶点。

中文关键词： 高血压；血管重塑；E1A激活基因阻遏子；血管紧张素II；基因表达

英文摘要： From the perspective of vascular homeostasis regulation, exploring novel protective molecules repressing hypertensive vascular remodeling has become an active hot spot in the research field of prevention and treatment of hypertension. Cellular repressor of E1A-stimulated gene (CREG) is a newly discoveried endogenous molecule implicated in regulation of vascular homeostasis. Our recent studies suggested that CREG expression was reduced prior to the development of vascular remodeling in response to angiotensin II (Ang II). In addition, CREG deficiency aggravates Ang II-induced vascular remodeling in hypertension, indicating that CREG may be a key molecule in regulating hypertensive vascular remodeling, and down-regulation of CREG expression in arteries may promote hypertension. To further clarify the role of CREG in the process of hypertensive vascular remodeling, we firstly intend to establish animal models of secondary hypertension based on wild-type mice. Then recombination human CREG protein will be applied to identify the role of CREG in the treatment of hypertension and vascular remodeling. Finally, we sought to uncover the key molecules mediating the down-regulation of CREG expression induced by Ang II from the view of modulation of transcription factors. We will find out the upstream regulatory mechanism and the key molecules mediating CREG expression inhibition in the process of hypertensive vascular remodeling. The findngs provide an important idea and new therapeutic target for the prevention and treatment of hypertension and vascular diseases caused by vascular homeostasis.

英文关键词： hypertension;vascular remodeling;cellular reprssor of E1A-stimulated genes;angiotensin II;gene expression