The influence of purinergic signaling on intracellular calcium signal transduction in podocytes in vivo

体内嘌呤信号对足细胞胞内钙信号转导的影响

• 批准号: 281647687
• 负责人: Dr. Matthias Johannes Hackl
• 金额: --
• 依托单位: Brain Research Institute
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/281647687?language=en
• 关键词: influence; purinergic; signaling; intracellular; calcium

The aim of this proposal is to study changes in podocyte calcium levels in reaction to purinergic and mechanic stimulation in healthy and diseased podocytes to delineate the effect of prior activation of purinergic signaling pathways in disease states. Our studies will provide more detailed insight into podocyte biology and in the long run help to develop new therapeutic strategies. If we are able to block long lasting calcium increases due to podocyte damage, we will be able to reduce podocyte loss and preserve kidney function of our patients. The proposed experiments utilize the newly available technique of in vivo calcium imaging of podocytes and will enable us to visualize calcium signal in podocytes after purinergic stimulation for the first time in physiologic and pathophysiologic states in the intact kidney. For this we will combine our expertise in in vivo imaging with state-of-the-art imaging technology and several new mouse models.The proposal will elucidate three questions :(1) To which extent leads preexisting activation of purinergic signaling pathways induced by disease models of nephrotic syndrom to increased calcium responses after purinergic stimulation and can this be blocked as a therapeutic approach ?(2) What kind of effect has the elimination of single purinergic receptors and calcium channels in podocytes on progression of kidney damage in different glomerular disease modells ?(3) What is the role of mechanical stress in podocyte foot processes in respect to calcium signaling in the microdomain of the foot processes and does this influence podocyte damage in disease models.

该方案的目的是研究健康和疾病足细胞对嘌呤能和机械刺激的反应中足细胞钙水平的变化，以揭示在疾病状态下预先激活嘌呤能信号通路的作用。我们的研究将为足细胞生物学提供更详细的见解，并从长远来看有助于开发新的治疗策略。如果我们能够阻止由于足细胞损伤而导致的长期钙增加，我们将能够减少足细胞损失，并保护患者的肾功能。这项实验利用了最新的足细胞体内钙成像技术，使我们能够首次在完整肾脏的生理和病理生理状态下观察嘌呤能刺激后足细胞内的钙信号。为此，我们将把我们在活体成像方面的专业知识与最先进的成像技术和几个新的小鼠模型结合起来。该提案将阐明三个问题：(1)在多大程度上导致肾病综合征疾病模型诱导的先前存在的嘌呤能信号通路在多大程度上导致嘌呤能刺激后钙反应增加，这作为一种治疗方法能否被阻止？(2)足细胞中单一的嘌呤能受体和钙通道的消除对不同肾小球疾病模型中肾脏损伤的进展有何影响？(3)机械应激在与钙信号有关的后足细胞过程中起什么作用在足部的微域过程中，这是否会影响疾病模型中的足细胞损伤。