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: 10210717
• 负责人: BIMAL N. DESAI
• 金额: $ 44.02万
• 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/10210717
• 关键词: Antibodies; Antigen Presentation Pathway; Antiviral Agents; 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，对衰老、受损和死亡细胞的及时和非炎症性清除是一种 处于组织动态平衡和炎症的十字路口的关键检查点。通过一种特殊形式的 吞噬作用，又称吞噬作用，是指组织内的吞噬细胞识别、吞噬和消化细胞身体。 而没有免疫系统的炎症和自毁激活。病毒感染细胞的细胞吞噬作用 身体也是抗原处理和呈递的先决条件，这是抗病毒的核心 免疫监控。吞噬的身体在噬泡体中被消化的机制 都高度依赖于钙信号，但其潜在的离子通道机制尚未被研究。我们的 初步数据表明，离子通道TRPM7在噬泡体成熟过程中起着至关重要的作用 以及它与溶酶体的最终融合。追寻这些诱人的线索现在已经奠定了强大的科学基础 基础假设：噬菌体的成熟是由M7V与 泡噬菌体并通过TRPM7通道活动在泡噬菌体膜上。在目标1中，确立 生理意义，我们将通过三种主要形式的胞吐作用来询问TRPM7的功能， 包括它在协调炎症信号方面的作用。在目标2中，我们提炼出关于本质和功能的关键见解 含TRPM7的囊泡在噬泡体成熟过程中。在目标3中，我们开发了一幅机械性的图景，说明如何 TRPM7被激活，以及这一活动如何控制噬泡体成熟。这项研究是概念性的 创新是因为它在未被研究的过程中揭开了涉及TRPM7的新的分子机制 噬泡体成熟。我们的研究也是向完整的生化特征迈进的第一步。 含TRPM7的囊泡(M7v)及其细胞生物学功能。技术创新包括新奇 转基因/基因编辑的小鼠品系，以及专门为询问M7V-噬泡体融合而设计的膜融合试验。从成熟阶段、分子水平解构噬泡体 结构和生物物理/生化活性可能推动TRPM7作为修饰组织的药物靶点 再生和抗病毒免疫。