Intra- and intercellular functions of redoxins during neuroinflammation

神经炎症过程中氧化还原素的细胞内和细胞间功能

• 批准号: 251964121
• 负责人: Privatdozent Dr. Carsten Berndt
• 金额: --
• 依托单位: Klinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/251964121?language=en
• 关键词: Intra; intercellular; functions; redoxins; during

Reversible oxidative thiol modifications are posttranslational modifications that control signal transduction making thiol switches of utmost significance for cellular functions. These switches are tightly regulated by redoxins - oxidoreductases of the thioredoxin family.In our proposal, we will address several aspects of this protein family that are still barely understood. We want to increase i) the number of characterized substrates and improve the understanding of ii) substrate specificity, iii) regulatory variety in addition to protein (in)activation, e.g. translocation or the interplay with other modifications, and the iv) spatio-temporal activity of redoxins, in particular extracellular functions of secreted redoxins. Based on our experiences in neurology and inflammation, we will synergistically analyze the functions of redoxins in neuroinflammation combining in vitro (cell cultures), ex vivo (primary cells, organotypic slice cultures), and in vivo models (zebrafish, mice) as well as samples from multiple sclerosis patients (brain slices, serum, cerebrospinal fluid). Within our two projects we will investigate redoxin-regulated processes and their underlying molecular mechanisms in glia cells during regeneration and immunomodulation. The regeneration from inflammation-induced brain damage and thereby the protection against neurological deficits depends on the migration of oligodendroglial progenitor cells towards lesions and their remyelinating capacity. We hypothesize that the identified glutaredoxin 2-induced differentiation block in a specific state (NG2-glia cells) enhances regeneration of neurons in different inflammation paradigms (autoimmunity, traumatic injury).To analyze the immunomodulatory mechanisms of secreted redoxins, we will investigate the secretion of redoxins by distinct cell types involved in neuroinflammation, in particular micro- and astroglia, and characterize their extracellular substrates and functions. Based on preliminary data, we propose secreted redoxins as new diagnostic tools for disease progression and effectiveness of immunomodulatory therapy which will be investigated by translating our findings to patients suffering from multiple sclerosis. In addition to the removal of oxidative thiol modifications by redoxins, we will also investigate the formation of these modifications on a mechanistic and physiologic level, focusing on the potential thiol oxidase lysine specific demethylase1. In summary, our two projects provide the first comprehensive investigation of redoxin functions in glial cells. Choosing the pathological condition of neuroinflammation, with emphasis on multiple sclerosis, our proposal will provide both translational results with direct clinical impact and fundamental mechanistic and functional insights into redoxins and redox regulation of intra- and intercellular signaling.

可逆的氧化巯基修饰是翻译后修饰，其控制信号转导，使得巯基开关对细胞功能具有极其重要的意义。这些开关是由氧化还原蛋白-硫氧还蛋白家族的氧化还原酶紧密调控的。在我们的建议中，我们将解决这个蛋白质家族的几个方面，仍然几乎不了解。我们希望增加i）表征的底物的数量并提高对ii）底物特异性的理解，iii）除了蛋白质（in）活化之外的调节多样性，例如易位或与其他修饰的相互作用，以及iv）氧化还原蛋白的时空活性，特别是分泌的氧化还原蛋白的细胞外功能。基于我们在神经学和炎症方面的经验，我们将协同分析氧化还原蛋白在神经炎症中的功能，结合体外（细胞培养），离体（原代细胞，器官型切片培养）和体内模型（斑马鱼，小鼠）以及多发性硬化症患者的样本（脑切片，血清，脑脊液）。在我们的两个项目中，我们将研究神经胶质细胞再生和免疫调节过程中氧化还原蛋白调节的过程及其潜在的分子机制。炎症诱导的脑损伤的再生以及由此对神经缺陷的保护取决于少突胶质祖细胞向病变的迁移及其髓鞘再生能力。我们推测，确定的谷氧还蛋白2诱导分化阻滞在一个特定的状态，（NG 2-胶质细胞）在不同炎症范例中增强神经元再生为了分析分泌的氧化还原蛋白的免疫调节机制，我们将研究参与神经炎症的不同细胞类型，特别是微胶质细胞和星形胶质细胞，并表征它们的细胞外底物和功能。基于初步数据，我们提出分泌型氧化还原酶作为疾病进展和免疫调节治疗有效性的新诊断工具，将通过将我们的研究结果转化为患有多发性硬化症的患者来研究。除了去除氧化巯基修饰的氧化还原蛋白，我们还将调查这些修饰的形成机制和生理水平上，专注于潜在的巯基氧化酶赖氨酸特异性脱甲基酶1。总之，我们的两个项目提供了第一个全面的调查神经胶质细胞中的氧化还原蛋白的功能。选择神经炎症的病理条件，重点是多发性硬化症，我们的建议将提供翻译结果与直接的临床影响和基本的机制和功能的见解氧化还原蛋白和氧化还原调节细胞内和细胞间的信号。