Molecular Mechanisms and Regulation Networks of TRPM8

TRPM8的分子机制和调控网络

• 批准号: 10569021
• 负责人: Wade D. Van Horn
• 金额: $ 37.68万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569021
• 关键词: Biological Process; Biophysics; Cells; Chemicals; Complement; Complex; Computational Technique; Data; Development; Disease; Drug Targeting; Electrophysiology (science); Explosion; Future; Genus Mentha; Goals; Health; Horns; Human; Ion Channel; Ion Channel Protein; Laboratories; Legal patent; Link; Maps; Membrane Proteins; Menthol; Modernization; Molecular; Obesity; Oncogenes; Outcome; Outcomes Research; Output; Pain; Physiology; Property; Proteins; Publications; Regulation; Research; Signal Transduction; Stimulus; Structure; TRP channel; Techniques; Therapeutic Intervention; cancer type; cold temperature; drug discovery; insight; interdisciplinary approach; patch clamp; prognostic; protein complex; protein function; research vision; sensor; stoichiometry; structural biology; therapeutic target; tumor progression

Project Summary/Abstract Overview of Research: The Van Horn lab primarily focuses on elucidating and understanding the molecular mechanisms that underlie membrane protein function in health and disease. To achieve these goals, the laboratory employs a modern state-of-the-art and interdisciplinary approach using biophysical, structural, computational, and functional techniques. We are experts in membrane protein biophysics and make use of advanced NMR studies combined with functional whole-cell patch-clamp electrophysiology. These orthogonal data are linked with Rosetta-based computational techniques to understand protein function. Our primary target is the TRPM8 ion channel which was initially identified as an oncogene that is prognostic for some types of cancer progression. More recently, it has become a focus for therapeutic intervention in pain and obesity. Complicating the potential application of TRPM8 therapies is that it is a molecular integrator that is activated by a number of diverse stimuli. For example, TRPM8 is the primary human cold sensor but is also activated by the chemical menthol from mint, both of which activate TRPM8 signaling networks. The ability to respond to several different stimuli in a polymodal manner makes TRPM8 studies crucial to delineate the independence and interdependence of molecular mechanisms that result in biological function and complicate its therapeutic targeting. In addition to direct stimulation by cold and menthol, TRPM8 is regulated by diverse proteins, including the membrane protein, PIRT, which in turn modulates TRPM8 activation by cold, menthol, and other stimuli. Beyond our research on direct activation of TRPM8 by cold and menthol, we focus on determining the mechanisms whereby PIRT modulates TRPM8 function. This has led to a number of contributions from our lab including, biophysical and structural characterization of TRPM8 and PIRT, TRPM8–PIRT complex stoichiometry, identification of species-dependent regulation, and central insight into molecular regulatory mechanisms. These efforts have led to strong scientific output, including publications, seminars, and patents. Five-year Goals: Broadly defined, we will identify how TRPM8 is directly activated by cold temperatures and other stimuli, map the allosteric networks that allow for polymodal function, and determine structures of TRPM8 and related membrane protein complexes of functional consequence. Research Vision: In the past 8 years, there has been an explosion of TRP channel structural biology with now ~100 discrete TRP channel structures. This represents tremendous development and output. Our research seeks to extend and complement the structural momentum to delineate fundamental mechanistic properties such as allostery, dynamics, and protein complex regulation that determines function. These TRPM8 outcomes are anticipated to have direct impacts on human health and disease but also to serve as a template that defines and identifies fundamental rules and properties of membrane protein function.

项目摘要/摘要 研究概述：Van Horn Lab主要侧重于阐明和理解分子 膜蛋白在健康和疾病中起作用的机制。为了实现这些目标， 实验室雇员使用生物物理，结构性的现代最先进和跨学科的方法 计算和功能技术。我们是膜蛋白生物物理学的专家，并使用 晚期NMR研究结合了功能性的全细胞贴片钳电生理学。这些正交 数据与基于罗塞塔的计算技术相关联，以了解蛋白质功能。我们的主要目标 是TRPM8离子通道，最初被识别为一种预后的癌基因 癌症进展。最近，它已成为治疗干预疼痛和肥胖症的重点。 使TRPM8疗法的潜在应用复杂化的是，它是一种分子积分器，被激活 许多潜水员刺激。例如，TRPM8是主要的人类冷传感器，但也被 来自薄荷的化学薄荷醇，两者都激活了TRPM8信号网络。回应几个的能力 以多种多态方式的不同刺激使TRPM8研究对于描述独立性至关重要 分子机制的相互依赖性，导致生物学功能并使其治疗复杂化 定位。除了寒冷和精神病的直接刺激外，TRPM8还受到多种蛋白质的调节，包括 膜蛋白Pirt又通过冷，精神病和其他刺激调节TRPM8激活。 除了通过冷和心态直接激活TRPM8的研究之外，我们还专注于确定 PIRT调节TRPM8功能的机制。这导致了我们实验室的许多贡献 包括TRPM8和PIRT的生物物理和结构表征，TRPM8 -PIRT复合体化学计量学， 鉴定物种依赖性调节以及对分子调节机制的中心见解。这些 努力导致了强大的科学产出，包括出版物，半手和专利。 五年目标：广义定义，我们将确定TRPM8如何直接被寒冷的温度和 其他刺激，绘制允许多型函数的变构网络，并确定TRPM8的结构 以及功能后果的相关膜蛋白复合物。 研究愿景：在过去的8年中，TRP渠道结构生物学爆炸了 〜100个离散的TRP通道结构。这代表了巨大的发展和产出。我们的研究 试图扩展并完成结构动量以描绘基本机械性能 作为决定功能的变构，动力学和蛋白质复合物调节。这些TRPM8结果是 预计会直接影响人类健康和疾病，但也可以作为定义和的模板 确定膜蛋白功能的基本规则和特性。