Regulation of Inflammatory Responses in the Cochlea

耳蜗炎症反应的调节

• 批准号: 8196791
• 负责人: FEDERICO KALINEC
• 金额: $ 37.42万
• 依托单位: HOUSE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196791
• 关键词: ATP-Binding Cassette Transporters; Address; Annexin A1; Annexins; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apical; Apoptosis; Auditory; Cavia; Cell Line; Cells; Clinical; Cochlea; Cochlear duct; Confocal Microscopy; Cytoplasm; Electron Microscopy; Freeze Fracturing; Glucocorticoids; Goals; Gold; Immune response; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intention; Intracellular Transport; Knowledge; Label; Leukocytes; Lipids; Lysophospholipids; Mediating; Migration Assay; Molecular Target; Myosin ATPase; Myosin Type II; Noise; Nonmuscle Myosin Type IIA; Organ; Organ of Corti; Outer Hair Cells; Pathway interactions; Phase; Play; Predisposition; Prevention; Proteins; Proteomics; Regulation; Resolution; Role; Sensorineural Hearing Loss; Site; Small Interfering RNA; Structure; Surface; Techniques; Technology; Testing; Tight Junctions; Tissues; Virus; cofilin; deafness; extracellular; hearing impairment; in vitro Model; in vivo Model; inhibitor/antagonist; insight; interest; knock-down; lysophosphatidic acid; migration; non-muscle myosin; prevent; public health relevance; restoration

DESCRIPTION (provided by applicant): Inflammation is a beneficial host response to foreign challenges or tissue injury that leads ultimately to the restoration of tissue structure and function. Leukocyte migration to sites of injury or infection is a defining step of inflammatory responses. In the mammalian cochlea, however, leukocyte migration into the auditory organ must be prevented as it may abolish the endocochlear potential by disrupting the tight-junction barrier at the organ of Corti luminal border (anatomically defined as the reticular lamina), leading to apoptosis of sensorimotor outer hair cells and irreversible, profound deafness. Thus, leukocytes are never found in the organ of Corti except in cases of extreme, irreversible cochlear damage. The mechanism used by the cochlea to prevent leukocyte migration is still unknown. The current gold standard clinical strategy to protect the organ of Corti against inflammatory damage is the local delivery of glucocorticoids. However, the mechanism by which glucocorticoids confer this protection is also unknown. The goal of this proposal is to fill these gaps in our knowledge, a crucial step in our quest to understand the regulation of inflammatory responses in the mammalian cochlea. Our preliminary studies provide strong support to the following hypotheses: 1) Annexin A1 (ANXA1), a pivotal regulator of many aspects of the innate and adaptive immune systems, have a major role in preventing leukocyte migration into the OC and facilitating the resolution phase of the inflammatory response; 2) glucocorticoids stimulate guinea pig Hensen cells to release ANXA1 via a myosin IIC-driven mechanism; and 3) Hensen cells store ANXA1 inside the prominent lipid droplets filling their cytoplasm. Thus, we propose to use the guinea pig as an in vivo model, an auditory cell line as an in vitro model, and a combination of non-overlapping techniques and methodological approaches to test these hypotheses by addressing the following Specific Aims: 1) Demonstrate that ANXA1 released by Hensen cells prevents leukocyte migration, 2) Elucidate the mechanism/s involved in the intracellular transport and release of ANXA1, and 3) Identify and characterize the mechanism/s involved in the storage and release of ANXA1 by Hensen cell lipid droplets. PUBLIC HEALTH RELEVANCE: Inflammatory responses in the cochlea, triggered by virus, noise, or ototoxic agents, can result in mild to profound hearing loss. The current gold standard clinical strategy to protect the auditory organ against inflammatory damage is the local delivery of glucocorticoids. However, the mechanism by which glucocorticoids confer this protection is still unknown. We are confident that by accomplishing the aims of the present proposal we will be able to provide critical insights about the mechanisms associated with inflammatory and anti-inflammatory responses in the cochlea, as well as identify new molecular targets for prevention and treatment of sudden sensorineural hearing loss.

描述（由申请人提供）：炎症是对外国挑战或组织损伤的有益宿主反应，最终导致组织结构和功能的恢复。白细胞迁移到受伤或感染部位是炎症反应的决定性步骤。然而，在哺乳动物的耳蜗中，必须防止白细胞迁移到听觉器官中，因为它可以通过破坏Corti Luminal边界器官（解剖学上定义为网状层）的紧密结屏屏障来消除内核的潜力，从而导致外毛细胞和irribles colleversibles and Irribles deververs deververs，呈现效果。因此，除了极端不可逆的耳蜗损害外，在Corti的器官中永远找不到白细胞。耳蜗用于预防白细胞迁移的机制仍然未知。糖皮质激素的局部递送，目前保护Corti免受炎症损害的器官的黄金标准临床策略。但是，糖皮质激素赋予这种保护的机制也未知。该提案的目的是在我们的知识中填补这些空白，这是我们寻求了解哺乳动物耳蜗炎症反应的关键步骤。我们的初步研究为以下假设提供了强有力的支持：1）膜联蛋白A1（Anxa1）是先天和适应性免疫系统许多方面的关键调节剂，在防止白细胞迁移到OC中并促进炎症反应的分辨率阶段具有重要作用； 2）糖皮质激素刺激豚鼠亨森细胞通过肌球蛋白IIC驱动的机制释放Anxa1； 3）Hensen细胞将Anxa1储存在填充其细胞质的突出脂质液滴中。 Thus, we propose to use the guinea pig as an in vivo model, an auditory cell line as an in vitro model, and a combination of non-overlapping techniques and methodological approaches to test these hypotheses by addressing the following Specific Aims: 1) Demonstrate that ANXA1 released by Hensen cells prevents leukocyte migration, 2) Elucidate the mechanism/s involved in the intracellular transport and release of ANXA1, and 3)识别并表征Hensen细胞脂质液滴储存和释放Anxa1所涉及的机制。 公共卫生相关性：由病毒，噪声或耳毒剂触发的耳蜗的炎症反应可能导致轻度至深远的听力损失。当前保护听觉器官免受炎症损害的当前黄金标准临床策略是糖皮质激素的局部输送。但是，糖皮质激素赋予这种保护的机制仍然未知。我们有信心，通过实现本提案的目标，我们将能够提供有关耳蜗中与炎症和抗炎反应相关的机制的关键见解，并确定预防和治疗突然感官听力损失的新分子靶标。