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，衰老，损坏和死细胞的及时和非炎症清除率是 在组织稳态和炎症的十字路口的关键检查点。通过专业形式的 吞噬作用，称为吞噬作用，组织居民的吞噬细胞识别，吞噬和消化细胞尸体 没有免疫系统的炎症和自我破坏性激活。病毒感染细胞的肿瘤病 尸体也是抗原加工和表现的先决条件，位于抗病毒的核心 免疫监视。吞噬的尸体在eferophagosom中消化的机制 高度依赖于Ca2+信号，但尚未研究基本的离子通道机制。我们的 初步数据表明，离子通道TRPM7在成熟的成熟中起着至关重要的作用 以及它与溶酶体的最终融合。追求这些诱人的潜在客户现在已经奠定了强大的科学 假设这一点的基础：efferophagosomy的成熟是由M7V融合到的 forephagosom体和通过trpm7通道活性在forphagosoms膜中。在目标1中建立 生理意义，我们将在三种主要形式的胚细胞增多症中询问TRPM7功能， 包括其在协调炎症信号中的作用。在AIM 2中，我们提炼有关性质和功能的关键见解 载脂体成熟中含有TRPM7的囊泡的囊泡。在AIM 3中，我们开发了一种机械图片 TRPM7被激活以及该活性如何控制造影症的成熟。这项研究在概念上是 创新的，因为它揭开了涉及TRPM7的新分子机械的研究。 efferophagosomy的成熟。我们的研究也是朝着完整的生化特征的第一个推动力 含TRPM7的囊泡（M7V）及其细胞生物学功能。技术创新包括小说 转基因/基因编辑的小鼠系和膜融合测定专门设计用于询问M7V伴随性杂物体融合。根据其成熟阶段来解构福音体的分子 结构和生物物理/生化活动可能会推进TRPM7作为修饰组织的药物靶标 再生和抗病毒免疫。