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Cellular and molecular mechanism underlying the modulation of neuronal excitability by heme and heme degradation products

血红素和血红素降解产物调节神经元兴奋性的细胞和分子机制

基本信息

批准号：
392037398
负责人：
Professor Dr. Stefan H. Heinemann
金额：
--
依托单位：
National Natural Science Foundation of China
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/392037398?language=en
关键词：
Cellular molecular mechanism underlying modulation

项目摘要

The blood pigment heme is well established as prosthetic group in hemoproteins; however, the functions of free heme (Fe2+-protoporphyrin IX) and its degradation products, such as carbon monoxide (CO), biliverdin, bilirubin, and an array of further catabolites summarized as bilirubin oxidation products (BOXes) are only beginning to be elucidated. Here we specifically investigate the cellular and molecular consequences of excessive presence of free heme and its degradation products (HHDPs), as found after traumatic brain injury and hemorrhagic strokes. Our firm preliminary results show that HHDPs markedly alter neuronal electrical excitability, potentially contributing to post traumatic epileptic and post hemorrhagic stroke seizures. Exploiting the complementary expertise in neurobiology, electrophysiology, functional imaging, and ion channel biophysics, as well as novel experimental tools and chemicals, this collaborative project aims at the elucidation of the cellular mechanisms (i) by which heme and its breakdown products affect the function of neurons of the rodent brain, (ii) which proteins are the major targets of HHDPs, and (iii) by which molecular mechanisms ion channels - which are of key importance for generating electrical neuronal signals - are affected by HHDPs. In a translational approach, we will furthermore relate the results obtained in the mouse brain and in in-vitro assays with patients´ single nucleotide polymorphisms in genes coding for HHDP-dependent signaling proteins. The research program will provide mechanistic insight into the interference of blood-derived messengers on neuronal signaling with significant relevance for posttraumatic neurological deficits.

血液色素血红素已被确定为血红素蛋白的辅基。然而，游离血红素 (Fe2+-原卟啉 IX) 及其降解产物，如一氧化碳 (CO)、胆绿素、胆红素以及一系列总结为胆红素氧化产物 (BOX) 的进一步分解代谢物的功能才刚刚开始被阐明。在这里，我们专门研究了在创伤性脑损伤和出血性中风后发现的游离血红素及其降解产物（HHDP）过量存在的细胞和分子后果。我们公司的初步结果表明，HHDP 显着改变神经元电兴奋性，可能导致创伤后癫痫和出血性中风后癫痫发作。该合作项目利用神经生物学、电生理学、功能成像和离子通道生物物理学方面的互补专业知识，以及新颖的实验工具和化学品，旨在阐明细胞机制（i）血红素及其分解产物影响啮齿动物大脑神经元功能的机制，（ii）哪些蛋白质是 HHDP 的主要目标，以及（iii）哪些蛋白质是 HHDP 的主要靶点。分子机制离子通道（对于产生电神经元信号至关重要）受到 HHDP 的影响。在转化方法中，我们还将在小鼠大脑和体外检测中获得的结果与患者编码 HHDP 依赖性信号蛋白的基因中的单核苷酸多态性联系起来。该研究项目将为血液来源的信使对神经元信号传导的干扰提供机制上的见解，这与创伤后神经功能缺陷具有显着相关性。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Divergent roles of haptoglobin and hemopexin deficiency for disease progression of Shiga-toxin-induced hemolytic-uremic syndrome in mice.

DOI：
10.1016/j.kint.2021.12.024
发表时间：
2022-01
期刊：
Kidney international
影响因子：
19.6
作者：
Wiebke Pirschel;Antonio N. Mestekemper;B. Wissuwa;N. Krieg;Sarah Kröller;Christoph Daniel;Florian Gunzer;E. Tolosano;Michael Bauer;Kerstin Amann;Stefan H Heinemann;S. Coldewey
通讯作者：
Wiebke Pirschel;Antonio N. Mestekemper;B. Wissuwa;N. Krieg;Sarah Kröller;Christoph Daniel;Florian Gunzer;E. Tolosano;Michael Bauer;Kerstin Amann;Stefan H Heinemann;S. Coldewey

Large-conductance Ca2+- and voltage-gated K+ channels form and break interactions with membrane lipids during each gating cycle