Investigation of the role of TRPML channel family and two-pore channel family members in intracellular fusion processes and the cation homeostasis of endolysosomal vesicles

TRPML通道家族和双孔通道家族成员在细胞内融合过程和内溶酶体囊泡阳离子稳态中的作用研究

• 批准号: 236242740
• 负责人: Professor Dr. Christian Michael Grimm
• 金额: --
• 依托单位: Walther-Straub-Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/236242740?language=en
• 关键词: Investigation; role; TRPML; channel; family

Cation homeostasis and pH regulation are essential for the function of endosomes, lysosomes and lysosome-related organelles (LROs) such as melanosomes. Although it has been known for a while how acidification of lysosomes and LROs is achieved, i.e. primarily via ATP-driven proton pumps (vacuolar H+-ATPases), still relatively little is known about the fine regulation of luminal pH in endosomes, lysosomes, melanosomes, or other LROs as well as the regulation of intraluminal cation concentrations such as calcium, sodium and potassium, but also heavy metals such as iron, zinc, copper for example. Further unclear is how the different endolysosomal fusion processes are regulated and how the calcium that appears to be necessary for most of such fusion processes is provided. Members of the TRP (transient receptor potential) family of non-selective cation channels, in particular the mucolipins TRPML1-3 as well as the two-pore channels (TPCs), TPC1 and TPC2, are preferentially expressed in the endolysosomal system and are likely to play decisive roles in the regulation of the above mentioned processes. By analyzing knock-out mouse models as well as protein-protein interactions the physiological role and function of TRPML channels and TPCs in such processes shall be investigated.

阳离子稳态和pH调节对于内体、溶酶体和溶酶体相关细胞器（LRO）如黑素体的功能是必不可少的。虽然已经知道溶酶体和LRO的酸化是如何实现的，即主要通过ATP驱动的质子泵虽然H-ATP酶（液泡H+-ATP酶）是一种重要的酶，但对于内体、溶酶体、黑素体或其他LRO中管腔pH的精细调节以及管腔内阳离子浓度（如钙、钠和钾）以及重金属（如铁、锌、例如铜。进一步不清楚的是，不同的内溶酶体融合过程是如何调节的，以及如何提供似乎是大多数这种融合过程所必需的钙。非选择性阳离子通道的TRP（瞬时受体电位）家族的成员，特别是粘脂TRPML 1 -3以及双孔通道（TPC）TPC 1和TPC 2，优先在内溶酶体系统中表达，并且可能在上述过程的调节中起决定性作用。通过分析敲除小鼠模型以及蛋白质-蛋白质相互作用，将研究TRPML通道和TPC在这些过程中的生理作用和功能。