Strial vascular pathology from acoustic trauma

声损伤引起的心房血管病理学

• 批准号: 9383753
• 负责人: Xiaorui Shi
• 金额: $ 42.54万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383753
• 关键词: Acoustic Trauma; Affect; Afferent Neurons; Aging; Animals; Auditory; Basement membrane; Biological; Biological Preservation; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Bromodeoxyuridine; Caliber; Cardiac; Cardiology; Cell Line; Cells; Clinical; Cochlea; Communication; Confocal Microscopy; Development; Disease; Ear; Edema; Electron Microscopy; Employee Strikes; Endothelial Cells; Energy Supply; Exposure to; Extravasation; Failure; Foundations; Functional disorder; Gene Delivery; Goals; Growth Factor; Hair Cells; Health; Hearing; Hearing problem; Heart; Hormones; Human; Hypoxia; Immunophenotyping; Impairment; In Vitro; Individual; Infarction; Injury; Kidney Diseases; Label; Labyrinth; Lateral; Lead; Life; Ligands; Loudness; Maintenance; Mediating; Membrane Proteins; Mesenchymal; Metabolic; Modeling; Molecular; Mus; Myocardial Infarction; Myofibroblast; Natural regeneration; Neonatal; Neurons; Noise; Nuclear; Organ; PDGFA gene; Pathologic; Pathology; Pericytes; Phenotype; Physiology; Platelet-Derived Growth Factor beta Receptor; Population; Production; Proliferating; Property; Proteins; Proto-Oncogene Proteins c-sis; Recovery; Regulation; Reporter; Research; Residual state; Resolution; Retina; Retinal; Role; Sensory; Signal Pathway; Signal Transduction; Site; Social isolation; Source; Stem cells; Stress; Stria Vascularis; Stroke; Structure; Sudden Deafness; System; Testing; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Transplantation; Trauma; Vascular Diseases; Vascular blood supply; Wound Healing; angiogenesis; base; blood perfusion; capillary; deafness; density; diabetic patient; fibrogenesis; hearing impairment; improved; inhibitor/antagonist; injured; matrigel; migration; network models; neurotrophic factor; novel; novel strategies; pigment epithelium-derived factor; platelet-derived growth factor BB; prevent; protein expression; receptor; repaired; restoration; sound; success; therapeutic target

PROJECT SUMMARY Energy supply to the ear is critical for hearing function since the ear is one of the highest energy consuming organs. Insufficient energy can result from insufficient blood flow to the cochlea contributing to a wide range of clinical hearing disorders such as loud sound-induced hearing loss, hearing loss related to ageing, and sudden deafness, which can largely impact the quality of human life by causing individual communication problems and social isolation. We believe that success in repair and regeneration of hearing function following loss of sensory cells requires parallel restoration or maintenance of an efficient blood supply. The proposed research is part of a longer range study on the role of pericytes in the physiology of the cochlea, but is specifically focused on the pericyte pathology that occurs in loud sound-induced lateral wall microcirculatory dysfunction. Pericytes are multipotent mesenchymal-like cells and are primarily located on microvessels. Normal function of pericytes is vital for blood flow regulation, vascular integrity, angiogenesis and tissue fibrogenesis. Pericyte pathology is profoundly associated with many organ diseases such as brain stroke, heart infarction, and retinal failure. Therapeutic targeting of pericytes has been considered a novel treatment for many of those clinical diseases. Cochlear pericytes are extremely vulnerable and sensitive to damage, but are critical for regulation of cochlear blood flow and maintaining tightness of the blood-labyrinth barrier in the stria vascularis. More specifically they are highly responsive to stress such as acoustic trauma. Upon exposure to loud sound, cochlear pericytes undergo striking changes in their biological properties, but the molecular mechanisms that underline those changes have not yet been studied. In this five year proposal, we will determine what molecular signals lead to loud sound-induced pericyte migration away from the capillaries and their phenotype changes. We will also determine whether transplantation of fresh pericytes such as neo-pericytes (derived from neonatal mice) to noise-damaged cochlea can repair loud sound-damaged microvessels and restore vascular function. The success of each aim will inevitably lead to the development of new protective and restorative therapies for a normal blood flow to cochlea― the critical foundation of hearing preservation or/and restoration.

项目摘要 耳朵的能源供应对于听力功能至关重要，因为耳朵是最高能量消耗之一 器官。流向耳蜗的血流不足可能导致能量不足，导致了广泛的范围 临床听力障碍，例如声音引起的听力损失，与衰老有关的听力损失和突然 耳聋，可以通过引起个人沟通问题在很大程度上影响人类生活的质量 和社会隔离。我们认为，损失后，修复和听力功能的再生成功 感觉细胞需要并行恢复或维持有效的血液供应。拟议的研究 是关于周细胞在耳蜗生理学中作用的长期研究的一部分，但特别是 专注于周围的病理学，该病理发生在响亮的声音诱导的侧壁微循环功能障碍中。 周细胞是多能间充质样细胞，主要位于微血管上。正常功能 周细胞对血流调节，血管完整性，血管生成和组织纤维发生至关重要。周围 病理学与许多器官疾病（例如脑部，心脏梗塞和视网膜）有着深远的联系 失败。对许多临床的治疗靶向周细胞的治疗靶向已被认为是一种新颖的治疗方法 疾病。人工耳蜗周细胞非常脆弱，对损害敏感，但对于调节至关重要 血管血管血管屏障的血液流量和维持血管血管障碍的紧密度。更多的 在暴露于大声的声音时，它们对诸如声学创伤之类的压力有很高的反应。 人工耳蜗的生物学特性发生了罢工变化，但是分子机制 强调这些变化尚未研究。在这五年的建议中，我们将确定什么 分子信号导致声音诱导的周细胞迁移远离毛细血管及其表型 更改。我们还将确定新鲜周细胞（如新鲜明物）的移植（源自 新生儿小鼠）到噪声损害的耳蜗可以修复大声的声音损坏的微血管并恢复血管 功能。每个目标的成功将不可避免地导致新受保护和恢复的发展 正常血液流向耳蜗的疗法 - 听力保存或恢复的关键基础。