Structure and Function of TRPV channels

TRPV通道的结构和功能

• 批准号: 10616166
• 负责人: Vera Moiseenkova-Bell
• 金额: $ 12.82万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616166
• 关键词: Biological; Biophysics; Cardiovascular Physiology; Cations; Cell physiology; Cells; Cryoelectron Microscopy; Distal convoluted renal tubule structure; Drug or chemical Tissue Distribution; Electron Microscopy; Electrophysiology (science); Epithelial Cells; Event; Exhibits; Flow Cytometry; Fluorescence Microscopy; Goals; Homeostasis; Human body; Immune; Immunity; Ions; Kidney; Label; Laboratories; Malignant Neoplasms; Mass Spectrum Analysis; Membrane Proteins; Methods; Molecular; Neurons; Permeability; Peroxidases; Pharmacology; Physiological; Play; Protein Biochemistry; Research; Role; Structure; TRP channel; TRPV channel; Vanilloid; apical membrane; interdisciplinary approach; member; microscopic imaging; neuron development; particle; programs; receptor

Title: Structure and Function of TRPV channels The long-term objective of this research program is to understand the molecular mechanisms of gating and cellular function of the two physiologically important members of the TRPV subfamily: transient receptor potential vanilloid 2 (TRPV2) and transient receptor potential vanilloid 5 (TRPV5). These channels belong to the same subfamily of TRP channels, nevertheless they exhibit striking differences in their tissue distribution, physiological function, cellular localization, ion permeation and selectivity, mechanisms of channel gating and pharmacology. TRPV2 is broadly expressed Ca2+-permeable non-selective cation channel, which plays a vital role in neuronal development, immunity, cardiovascular physiology, and cancer. TRPV5 is a highly selective Ca2+ channel, that is only expressed on the apical membrane of kidney distal convoluted tubule epithelial cells and plays a critical role in Ca2+ homeostasis in the human body. This proposal is built on the major advances achieved by my group in understanding TRPV2 and TRPV5 channels structures, molecular details of gating and cellular function in the last 10 years. The overall goal of this proposal is to further understand how TRPV2 and TRPV5 channels are gated by endogenous and exogenous modulators at the atomic level; and to elucidate TRPV2 channel precise molecular function in neuronal development and immunity. To answer these questions, we will employ cutting- edge multidisciplinary approaches available to our laboratory, including membrane protein biochemistry and biophysics, single-particle cryo-EM, peroxidase-catalyzed proximity labeling and mass spectrometry, cryoAPEX for electron microscopy imaging, flow cytometry, confocal fluorescence microscopy, and functional characterization by electrophysiological and cell biological methods. This information would be critical in our understanding of TRPV channels physiological and pathophysiological roles.

标题：TRPV频道的结构和功能 该研究计划的长期目标是了解门控和 TRPV亚家族的两个生理上重要成员的细胞功能：瞬态受体电位 香草素2（TRPV2）和瞬态受体电势香草素5（TRPV5）。这些渠道属于同一渠道 TRP通道的亚家族，尽管如此，它们在组织分布中表现出明显的差异，生理 功能，细胞定位，离子渗透和选择性，通道门控机制和药理学的机制。 TRPV2广泛表达Ca2+可渗透的非选择性阳离子通道，在神经元中起着至关重要的作用 发育，免疫力，心血管生理和癌症。 TRPV5是一个高度选择性的Ca2+通道， 仅在肾脏远端曲折小管上皮细胞的顶膜上表达并发挥关键 在人体中的Ca2+稳态中的作用。该提议建立在我小组取得的重大进步之上 在了解TRPV2和TRPV5通道结构时，门控和细胞功能的分子细节 最近10年。该提案的总体目标是进一步了解TRPV2和TRPV5频道的方式 在原子水平上由内源和外源调节剂门控；并阐明TRPV2通道精确 分子功能在神经元发育和免疫力中。为了回答这些问题，我们将采用挑战 - 我们实验室可用的边缘多学科方法，包括膜蛋白生物化学和 生物物理学，单粒子冷冻EM，过氧化物酶催化的接近标记和质谱法，冷冻蛋白 用于电子显微镜成像，流式细胞术，共聚焦荧光显微镜和功能性 通过电生理和细胞生物学方法的表征。这些信息对我们至关重要 了解TRPV通道的生理和病理生理作用。