Macrophage Response to Otic Pathology

巨噬细胞对耳部病理学的反应

• 批准号: 10517866
• 负责人: Mark Warchol
• 金额: $ 43.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517866
• 关键词: Acoustic Nerve; Acute; Affect; Afferent Neurons; Brain; Cause of Death; Cell Death; Cell Survival; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Cochlea; Cochlear Implants; Cochlear implant procedure; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Dizziness; Eating; Effector Cell; Epithelial; Equilibrium; Excision; Exposure to; Family; Hair Cells; Head Movements; Hearing; Homeostasis; Human; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune System; Inner Ear Infection; Inner Hair Cells; Knowledge; Labyrinth; Lesion; Mechanics; Mediating; Membrane; Modeling; Morphology; Motion; Mus; Natural Immunity; Natural regeneration; Neomycin; Organ; Pathology; Peripheral; Phagocytes; Phagocytosis; Phosphatidylserines; Phosphotransferases; Pilot Projects; Play; Population; Process; Recovery of Function; Role; Sensory; Sensory Hair; Signal Pathway; Signal Transduction; Site; Stereotyping; Supporting Cell; Surface; System; Testing; Time; Tissues; Utricle structure; Vertebrates; Vertigo; Vestibular Hair Cells; Vestibular Nerve; Vestibular loss; Virus Diseases; Zebrafish; base; cell injury; cell type; clinically relevant; equilibration disorder; experience; experimental study; hair cell regeneration; implantation; injured; injury recovery; lateral line; macrophage; macula; member; method development; mouse model; neonatal mice; neuromast; noise exposure; normal aging; ototoxicity; ototoxin; prenatal; prevent; receptor; recruit; repaired; response; sound; tissue repair; vibration

The senses of hearing and balance are mediated by the cochlea and vestibular organs of the inner ear. In these organs, mechanical motion (generated either by sound vibrations or by head movements) is detected by sensory hair cells and transmitted to the brain by the auditory and vestibular nerves. Hair cells are essential for sensory function, but can be injured by noise exposure, ototoxicity or infections, and are also lost as a consequence of normal aging. After injury, the timely removal of cellular debris from the sensory epithelium helps promote repair and homeostasis. This process is mediated by two distinct cell types: (1) Supporting cells, which can engulf cellular debris and – in nonmammalian vertebrates – generate replacement hair cells, and (2) Macrophages, which are effector cells of the innate immune system that also recognize and engulf dying cells. Supporting cells are present in all hair cell-containing epithelia. The tissues of the inner ear also contain resident populations of macrophages, and macrophage-mediated inflammation occurs after most types of otic injury. When responding to hair cell injury, it is critical that both supporting cells and macrophages correctly distinguish between healthy and dying cells, and then target and remove only those cells that are irreversibly damaged. A key objective of this project is to understand how this process occurs. One set of experiments will examine a signaling pathway known to be essential for evoking phagocytic responses in macrophages and other cell types, but has not been previously studied in the inner ear. In addition, we will determine whether inhibiting phagocytosis after acute injury may permit some damaged hair cells to survive, and whether the engulfment of injured hair cells is an important trigger for sensory regeneration. Studies will employ both mammalian and zebrafish models, in order to best utilize the unique advantages of both systems. A second set of experiments will enhance our very limited knowledge of the role of inflammation in the vestibular organs. Projects will focus on two clinically relevant situations. First, it is known that prenatal infection with cytomegalovirus (CMV) can cause developmental deficits in both hearing and balance, but the underlying mechanisms are completely unknown. Using a validated mouse model, we have shown that CMV infection leads to a massive inflammatory response in the vestibular maculae, which is accompanied by phagocytosis of sensory cells. We will determine whether this inflammation is the cause of CMV-induced pathology and also whether macrophages transport CMV into the vestibular periphery. Additional studies will characterize vestibular injury and inflammation in a mouse model of cochlear implantation. Completion of the studies will greatly enhance current knowledge of the cellular signals that regulate inflammation in the inner ear. Such knowledge will permit development of methods for modulating such inflammation, so as to reduce pathology and enhance functional recovery after injury.

听觉和平衡感由内耳的耳蜗和前庭器官介导。在 这些器官，机械运动（由声音振动或头部运动产生）被检测到 感觉毛细胞，并通过听觉和前庭神经传递到大脑。毛细胞对于 感觉功能，但也可能因噪声暴露、耳毒性或感染而受损， 正常老化的结果。损伤后，及时清除感觉上皮细胞碎片 有助于促进修复和体内平衡。这一过程由两种不同的细胞类型介导：（1）支持细胞， 它可以吞噬细胞碎片，并在非哺乳类脊椎动物中产生替代毛细胞，以及（2） 巨噬细胞是先天免疫系统的效应细胞，也能识别和吞噬垂死细胞。 支持细胞存在于所有含毛细胞的上皮细胞中。内耳的组织也含有 巨噬细胞和巨噬细胞介导的炎症发生后，大多数类型的耳 损伤当对毛细胞损伤作出反应时，支持细胞和巨噬细胞正确地 区分健康和垂死的细胞，然后只针对和去除那些不可逆的细胞， 损坏这个项目的一个关键目标是了解这个过程是如何发生的。一组实验将 检查已知对于引起巨噬细胞中的吞噬反应至关重要的信号传导途径， 其他细胞类型，但以前没有在内耳中研究过。此外，我们将确定是否 抑制急性损伤后的吞噬作用可能允许一些受损的毛细胞存活， 损伤毛细胞的吞噬是感觉再生的重要触发因素。研究将采用两者 哺乳动物和斑马鱼模型，以便最好地利用这两个系统的独特优势。第二组 这些实验将增强我们对炎症在前庭器官中作用的非常有限的知识。 项目将集中在两个临床相关的情况。首先，众所周知，产前感染 巨细胞病毒（CMV）可导致听力和平衡的发育缺陷，但潜在的 机制完全未知。使用经过验证的小鼠模型，我们已经表明CMV感染 导致前庭斑的大量炎症反应，伴随着对 感觉细胞我们将确定这种炎症是否是CMV诱导的病理学的原因， 巨噬细胞是否将CMV转运到前庭外周。其他研究将描述 前庭损伤和炎症的小鼠模型的耳蜗植入。完成研究将 大大增强了目前对调节内耳炎症的细胞信号的认识。等 知识将允许开发用于调节这种炎症的方法，从而减少病理学 促进损伤后功能恢复。