TRPM7 at the Crossroads of Tissue Homeostasis and inflammation

TRPM7 处于组织稳态和炎症的十字路口

• 批准号: 10409807
• 负责人: BIMAL N. DESAI
• 金额: $ 36.8万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10409807
• 关键词: Antibodies; Antigen Presentation Pathway; Apoptotic; Architecture; Biochemical; Biological Assay; Biological Process; Biophysics; Cathepsins; Cell Nucleus; Cell physiology; Cells; Communicable Diseases; Complement; Data; Disease; Drug Targeting; Eating; Foundations; Genes; Heart; Homeostasis; Immune system; Immunity; Immunologic Surveillance; Immunologics; Inflammation; Inflammatory; Investigation; Ion Channel; Lead; Lysosomes; Mediating; Membrane; Membrane Fusion; Modeling; Molecular; Mus; NADPH Oxidase; Nature; Necrosis; Output; Phagocytes; Phagocytosis; Phagolysosome; Phagosomes; Phosphatidylserines; Phosphotransferases; Physiological; Play; Population; Process; Proteins; Reagent; Regulation; Research; Role; Secretory Vesicles; Signal Transduction; Small Interfering RNA; Techniques; Testing; Time; Tissues; Transgenic Organisms; Vesicle; Viral; Virus; Virus Diseases; Vision; age related; antigen processing; antiviral immunity; body system; design; endonuclease; experimental study; immune activation; in vivo; innovation; insight; macrophage; new therapeutic target; novel; novel therapeutic intervention; pathogen; prevent; senescence; tissue regeneration; trafficking; vacuolar H+-ATPase; wound healing

In all organ systems, timely and non-inflammatory clearance of senescent, damaged and dead cells is a crucial checkpoint at the crossroads of tissue homeostasis and inflammation. Through a specialized form of phagocytosis, termed efferocytosis, the tissue-resident phagocytes recognize, engulf and digest cell corpses without the inflammatory and self-destructive activation of the immune system. Efferocytosis of virally infected cell corpses is also a prerequisite to antigen processing and presentation that lies at the heart of anti-viral immunosurveillance. The mechanisms through which the engulfed corpses are digested in the efferophagosome are highly dependent on Ca2+-signaling but underlying ion channel mechanisms have not been studied. Our preliminary data indicates that the ion channel TRPM7 plays a crucial role in the maturation of the efferophagosome and its ultimate fusion with the lysosomes. Pursuing these tantalizing leads has now laid a strong scientific foundation to hypothesize that: Efferophagosome maturation is controlled by the fusion of M7Vs to the efferophagosome and through TRPM7 channel activity in the efferophagosome membrane. In Aim 1, to establish the physiological significance, we will interrogate TRPM7 function across three main forms of efferocytosis, including its role in coordinating inflammatory signals. In Aim 2, we distill key insights about the nature and function of TRPM7-containing vesicles in efferophagosome maturation. In Aim 3, we develop a mechanistic picture of how TRPM7 is activated and how this activity controls efferophagosome maturation. This research is conceptually innovative because it unravels new molecular machinery involving TRPM7 in the understudied process of efferophagosome maturation. Our research is also the first thrust toward a complete biochemical characterization of TRPM7-containing vesicles (M7Vs) and their cell biological function. Technical innovations include novel transgenic/gene-edited mouse lines, and membrane fusion assays designed specifically to interrogate M7V-efferophagosome fusion. Deconstructing the efferophagosome in terms of its maturation stages, molecular architecture, and biophysical/biochemical activities may advance TRPM7 as a drug target to modify tissue regeneration and anti-viral immunity.

在所有器官系统中，及时、非炎症性清除衰老、受损和死亡细胞是一个关键因素。 组织稳态和炎症十字路口的关键检查点。通过专门的形式 吞噬作用，称为胞吞作用，组织驻留的吞噬细胞识别、吞噬和消化细胞尸体 没有免疫系统的炎症和自我毁灭性激活。病毒感染细胞的胞吞作用 尸体也是抗原加工和呈递的先决条件，而抗原加工和呈递是抗病毒的核心 免疫监视。被吞噬的尸体在吞噬体中被消化的机制 高度依赖 Ca2+ 信号传导，但潜在的离子通道机制尚未研究。我们的 初步数据表明离子通道TRPM7在吞噬体的成熟中起着至关重要的作用 及其与溶酶体的最终融合。追求这些诱人的线索现已奠定了强大的科学基础 假设的基础：吞噬体的成熟是由 M7Vs 与 吞噬体并通过吞噬体膜中的 TRPM7 通道活性。在目标 1 中，建立 为了了解其生理意义，我们将探讨 TRPM7 在三种主要形式的胞吞作用中的功能， 包括其在协调炎症信号中的作用。在目标 2 中，我们提炼出有关性质和功能的关键见解 含有 TRPM7 的囊泡在吞噬体成熟过程中的变化。在目标 3 中，我们绘制了一幅关于如何 TRPM7 被激活以及该活性如何控制吞噬体成熟。这项研究在概念上 创新是因为它在正在研究的过程中揭示了涉及 TRPM7 的新分子机制 吞噬体成熟。我们的研究也是全面生化表征的第一个推动力 含 TRPM7 的囊泡 (M7V) 及其细胞生物学功能。技术创新包括新颖 转基因/基因编辑小鼠品系，以及专门设计用于检测 M7V-吞噬体融合的膜融合测定。从成熟阶段、分子水平角度解构吞噬体 结构和生物物理/生化活性可能会促进 TRPM7 作为修饰组织的药物靶点 再生和抗病毒免疫。