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The Effects of CD40 Ligand Deficiency on Vascular Dysfunction, Immunoglobulin Production and Lymph Capillary Density in a Murine Model for High-Salt Diet

CD40 配体缺陷对高盐饮食小鼠模型中血管功能障碍、免疫球蛋白产生和毛细淋巴管密度的影响

基本信息

批准号：
290587856
负责人：
Dr. Steffen Daub
金额：
--
依托单位：
Zentrum für Kardiologie
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/290587856?language=en
关键词：
Effects CD40 Ligand Deficiency Vascular

项目摘要

A high-salt diet is the norm in Western society. It has been shown to be associated with vascular dysfunction, hypertension and increased cardiovascular mortality and morbidity. While this is a widely known and well-proven fact, the mechanism behind the association between high-salt diet and endothelial dysfunction, insulin resisistance, vascular stiffness, metabolic syndrome, attenuated blood pressure dipping and increased inflammation remains incompletely understood. Traditionally, the milieu intérieur, as proposed by Claude Bernard over a century ago, has coined our unterstanding of sodium homeostasis within the body. This model envolves an equilibrium between extracellular electrolyte and water content. Recently, Jens Titze and colleagues were able to revolutionize our understanding of sodium homeostasis, showing that extracellular Sodium is being stored without subsequent water retention, a phenomenon observed in animals fed a high-salt diet. An increase in extracellular Sodium has been shown to lead to the activation of a transcription factor named TonEBP, which is able to translate an excess of interstitial sodium into a (patho-)physiological response. It is of yet unclear, however, which genes and proteins play a part in this translation. With the CD40 Ligand being crucial to the interaction between T cells and B cells, the formation of atherosclerotic plaques and their invasion by cells of the immune system, in silico the gene-sequence belonging to CD40 Ligand is a target for the aforementioned transcription factor TonEBP. Therefore it is highly likely that the (patho-)physiological effects in animals fed a high-salt diet are due to the interaction between TonEBP and the promotor region of CD40 Ligand.In this study, I would like to assess this Interaction in mice lacking CD40 Ligand in three ways: 1. CD40L-/- mice will show impaired immunoglobulin production when subjected to TNP-KHL immunization while fed a high-salt diet. 2. CD40L-/- mice will display reduced lymph capillary density in skin, resulting in impaired Na+ clearance when fed a high-salt diet. 3. CD40L-/- mice fed a high-salt diet will accumulate as much or more osmotically inactive Na+ in the interstitium than their wild-type littermates, thus resulting in an increase in TonEBP activity. While this will cause endothelial dysfunction in wild type animals as mentioned above, CD40L-deficiency will protect the animals from the harmful effects of the transcription factor, thus rendering endothelial function unimpaired.

高盐饮食是西方社会的常态。它已被证明与血管功能障碍、高血压和心血管疾病死亡率和发病率增加有关。虽然这是一个众所周知的事实，但高盐饮食与内皮功能障碍、胰岛素抵抗、血管僵硬、代谢综合征、血压下降和炎症增加之间的关联机制仍不完全清楚。传统上，克劳德·伯纳德在一个多世纪前提出的“体内环境”理论，创造了我们对体内钠稳态的理解。该模型涉及细胞外电解质和水含量之间的平衡。最近，Jens Titze和他的同事们彻底改变了我们对钠体内平衡的理解，他们发现细胞外的钠被储存起来，没有随后的水潴留，这是在喂食高盐饮食的动物中观察到的现象。细胞外钠的增加已被证明会导致一种名为TonEBP的转录因子的激活，这种转录因子能够将过量的间质钠转化为一种（病理）生理反应。然而，目前尚不清楚哪些基因和蛋白质在这种翻译中起作用。CD40配体对于T细胞和B细胞之间的相互作用、动脉粥样硬化斑块的形成以及免疫系统细胞的入侵至关重要，因此，属于CD40配体的基因序列是上述转录因子TonEBP的靶标。因此，高盐饮食对动物的（病理）生理影响很可能是由于TonEBP与CD40配体启动子区域的相互作用。在这项研究中，我想通过三种方式评估缺乏CD40配体的小鼠的这种相互作用：1。CD40L-/-小鼠在高盐饮食中接受TNP-KHL免疫后，免疫球蛋白的产生会受损。2. 高盐饮食会导致CD40L-/-小鼠皮肤淋巴毛细血管密度降低，导致Na+清除受损。3. 喂食高盐饮食的CD40L-/-小鼠会在间质中积累与野生型同伴一样多或更多的渗透性非活性Na+，从而导致TonEBP活性增加。如上所述，这将导致野生型动物的内皮功能障碍，而cd40l缺乏将保护动物免受转录因子的有害影响，从而使内皮功能不受损害。