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、受损和死亡细胞的及时和非炎症性清除是一种有效的方法。 在组织稳态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，称为吞噬作用，组织中的吞噬细胞识别，吞噬和消化细胞尸体 免疫系统的炎症和自我破坏性激活。病毒感染细胞的胞吐作用 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。 免疫监视吞噬体消化被吞噬的尸体的机制 高度依赖于Ca 2+信号，但尚未研究潜在的离子通道机制。我们 初步数据表明，离子通道TRPM 7在噬菌体的成熟中起着至关重要的作用 最终与溶酶体融合追踪这些诱人的线索已经奠定了强大的科学基础 假设的基础是：泡噬体成熟是由M7 V与M7 V的融合控制的。 TRPM 7通道在噬菌体膜上起重要作用。目标1：建立 生理意义，我们将询问TRPM 7在三种主要形式的红细胞增多症中的功能， 包括其在协调炎症信号中的作用。在目标2中，我们提取了关于性质和功能的关键见解 含TRPM 7的囊泡在噬菌体成熟中的作用。在目标3中，我们制定了一个机械图，说明如何 TRPM 7被激活以及这种活性如何控制噬菌体成熟。这项研究在概念上 创新，因为它揭示了新的分子机制，涉及TRPM 7在未充分研究的过程， 噬菌体成熟。我们的研究也是第一次推动一个完整的生化表征 TRPM 7囊泡（M7 Vs）的研究进展及其细胞生物学功能。技术创新包括创新 转基因/基因编辑的小鼠系，和专门设计用于询问M7 V-噬菌体融合的膜融合测定。从成熟阶段的角度解构噬菌体， 结构和生物物理/生物化学活性可以促进TRPM 7作为药物靶点来修饰组织 再生和抗病毒免疫。