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Stress and vascular risk --Elucidating the associations between endothelial dysfunction, telomerase activity, increased susceptibility of the brain to injury and hyperactivity of the neuroendocrine stress axis

压力和血管风险——阐明内皮功能障碍、端粒酶活性、大脑对损伤的易感性增加和神经内分泌应激轴过度活跃之间的关联

基本信息

批准号：
266306077
负责人：
Professorin Dr. Karen Gertz, since 7/2017
金额：
--
依托单位：
Abteilung für Experimentelle Neurologie (CCM)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/266306077?language=en
关键词：
Stress vascular risk Elucidating associations

项目摘要

Affective disorders and psychosocial stress confer an increased risk for vascular events such as myocardial infarction or stroke. They also result in increased morbidity and mortality as well as in worse functional outcome after an ischemic lesion. Here, the effects of stress on the vascular system will be investigated in two murine stress models (chronic stress and maternal-deprivation paradigms). In previous studies, we were able to show that chronic stress exacerbates the ischemic damage in a well-characterized vascular lesion model (i.e., stroke). The central hypothesis of this proposal is that chronic stress results in endothelial dysfunction, which in turn bestows a special vulnerability to vascular events. We speculate that altered telomerase activity may be an important underlying molecular mechanism, leading to downstream changes in DNA damage response pathways, increased apoptosis and a limited ability of the endothelium to proliferate in response to an ischemic stimulus. We will study dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis as a potentially crucial mediator of the effects of stress on the endothelium. Finally, to gain further mechanistic insight, we will use lentiviral gene transfer to modulate the expression of the protein component of the telomerase enzyme (TERT) specifically in endothelial cells.

情感障碍和心理社会压力会增加心肌梗死或中风等血管事件的风险。它们还导致发病率和死亡率增加以及缺血性病变后功能结局更差。在这里，将在两个小鼠应激模型（慢性应激和母亲剥夺范式）中研究应激对血管系统的影响。在以前的研究中，我们能够证明慢性应激在充分表征的血管病变模型中加剧缺血性损伤（即，中风）。该建议的中心假设是，慢性应激导致内皮功能障碍，这反过来又赋予了血管事件的特殊脆弱性。我们推测，改变端粒酶活性可能是一个重要的潜在的分子机制，导致下游的DNA损伤反应途径的变化，增加细胞凋亡和有限的能力，内皮细胞增殖响应缺血刺激。我们将研究下丘脑-垂体-肾上腺（HPA）轴的失调作为一个潜在的关键调解人的影响，压力对内皮细胞。最后，为了获得进一步的机制见解，我们将使用慢病毒基因转移来调节特异性地在内皮细胞中的端粒酶（TERT）的蛋白组分的表达。