Coordination Funds

协调基金

• 批准号: 441865721
• 负责人: Professor Dr. Dominik Oliver
• 金额: --
• 依托单位: Institut für Physiologie und Pathophysiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/441865721?language=en
• 关键词: Coordination; Funds

The Solute Carrier family 26 (SLC26) includes functionally versatile anion transporters present throughout all kingdoms of life. The human genome encodes ten functional homologs, several of which are causally associated with severe human diseases, such as chloride losing diarrhea, hypothyroidism, male infertility, skeletal malformation, brain edema, or deafness. Association with human diseases substantiate the high physiological and pathophysiological importance of SLC26 transporters, yet fundamental principles of their function, regulation, and role in cell and organ physiology remain poorly understood. Progress has been slowed by missing structural information at the molecular level and lack of suitable model systems at the physiological level. The recent determination of the structural architecture of SLC26 proteins and technical developments towards improved model systems represent major breakthroughs that will now allow us to analyze selected SLC26 isoforms at unprecedented depth and level of detail.The integrative goal of this Research Unit is the analysis of structure, function, and regulation of selected SLC26 isoforms in both reduced molecular and complex physiological environments. We will focus particularly on the SLC26 isoforms A2, A3, A6, A9, and A11 with pathophysiological relevance in the kidney and intestine as prototypic epithelial transport organs. The Research Unit will (i) elucidate the structural basis of transport and its regulation by determining the atomic structures of SLC26 proteins, (ii) perform detailed structure-function analysis, (iii) bridge structural and functional data via molecular dynamics simulations for predicting transport mechanisms, (iv) determine how selected SLC26 transporters are regulated in cells by trafficking and by protein-protein interactions, and (v) dissect the function of these specific SLC26 homologs in solute transport in gastrointestinal and renal epithelia.State-of-the-art technical approaches used in an interdisciplinary manner will be key to achieve these aims. These include single-particle cryo-EM, all-atom molecular dynamics simulations, electrophysiology, and fluorescence spectroscopy at the molecular level. Cellular biology will be addressed by interaction proteomics and complexome profiling combined with live-cell fluorescence microscopy. For elucidating physiology and pathophysiology at the systemic level, we will study human organoids as a near-native in-vitro approach as well as new conditional mouse models. A platform for generation of nanobodies directed against all targeted SLC26 isoforms will provide pivotal tools for structure determination, proteomics and imaging.We expect that the results of this research program will reveal novel molecular mechanisms, cellular pathways, and organ functions, which will be accessible to molecular interventions and together may provide a foundation for future translational research.

溶质载体家族26（SLC 26）包括存在于所有生命王国中的功能多样的阴离子转运蛋白。人类基因组编码10种功能同源物，其中几种与严重的人类疾病有因果关系，如失氯性腹泻、甲状腺功能减退、男性不育、骨骼畸形、脑水肿或耳聋。与人类疾病的关联证实了SLC 26转运蛋白的高度生理和病理生理学重要性，但其功能、调节和在细胞和器官生理学中的作用的基本原理仍然知之甚少。由于缺少分子水平的结构信息和缺乏生理水平的合适模型系统，进展缓慢。SLC 26蛋白质结构的最新测定和改进模型系统的技术发展代表了重大突破，这将使我们能够以前所未有的深度和详细程度分析所选SLC 26亚型。该研究单位的综合目标是分析所选SLC 26亚型在分子和复杂生理环境中的结构、功能和调控。我们将特别关注SLC 26亚型A2、A3、A6、A9和A11，它们在作为原型上皮转运器官的肾脏和肠中具有病理生理学相关性。研究单位将（i）通过确定SLC 26蛋白的原子结构阐明运输及其调节的结构基础，（ii）进行详细的结构-功能分析，（iii）通过分子动力学模拟桥接结构和功能数据以预测运输机制，（iv）确定如何通过运输和蛋白质-蛋白质相互作用在细胞中调节选定的SLC 26转运蛋白，以及（v）剖析这些特异性SLC 26同源物在胃肠和肾上皮中的溶质转运中的功能。这些包括单粒子冷冻EM，全原子分子动力学模拟，电生理学和荧光光谱在分子水平上。细胞生物学将通过相互作用蛋白质组学和复合体分析与活细胞荧光显微镜相结合来解决。为了阐明系统水平的生理学和病理生理学，我们将研究人类类器官作为一种近天然的体外方法以及新的条件性小鼠模型。针对所有靶向SLC 26亚型的纳米抗体的生成平台将为结构确定、蛋白质组学和成像提供关键工具。我们期望该研究计划的结果将揭示新的分子机制、细胞通路和器官功能，这些将可用于分子干预，并为未来的转化研究提供基础。