Fibrovascular coupling in the cochlea and pericyte recruitment after noise

噪声后耳蜗中的纤维血管耦合和周细胞募集

• 批准号: 8079462
• 负责人: Xiaorui Shi
• 金额: $ 37.27万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079462
• 关键词: Action Potentials; Affect; Animals; Astrocytes; Attenuated; Blood; Blood Flow Velocity; Blood Vessels; Blood capillaries; Blood flow; Bone Marrow Cell Transplantation; Brain; Bromodeoxyuridine; Calcium; Caliber; Clinical; Clinical Management; Clinical Treatment; Cochlea; Computer software; Confocal Microscopy; Coupled; Coupling; Custom; Development; Dinoprostone; Disease; Electrophysiology (science); Enzyme-Linked Immunosorbent Assay; Extravasation; Fluid Balance; Foundations; Functional disorder; Goals; Hair Cells; Hearing; Hearing problem; Image; Immune; Immunoglobulin G; In Vitro; Ions; Knockout Mice; Knowledge; Label; Laboratories; Labyrinth; Ligaments; Link; Measures; Medical; Metabolic; Methods; Microcirculation; Molecular; Neuroglia; Neurons; Nitric Oxide; Nitric Oxide Pathway; Noise; Noise-Induced Hearing Loss; Pathology; Pathway interactions; Pericytes; Permeability; Physiology; Play; Population; Presbycusis; Production; Prostaglandin-Endoperoxide Synthase; Proto-Oncogene Proteins c-sis; Recovery; Recycling; Regional Blood Flow; Regulation; Research; Retina; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensorineural Hearing Loss; Serum Proteins; Signal Pathway; Signal Transduction; Smooth Muscle; Staining method; Stains; Stem cells; Stria Vascularis; Testing; Tinnitus; Transplantation; Trauma; Up-Regulation; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular blood supply; Western Blotting; base; capillary; density; disorder prevention; foot; hearing impairment; in vivo; inner ear diseases; intravital fluorescence microscopy; meetings; photolysis; public health relevance; repaired; round window; sound

DESCRIPTION (provided by applicant): Cochlear microcirculation is essential for normal hearing, with reduction of cochlear blood flow and disruption of blood-labyrinth barrier (BLB) involved in a number of hearing disorders. Development of new treatments for vascular-related hearing loss requires a better understanding of control over cochlear blood flow (CBF) and repair of the BLB. In particular, we need to understand the local cellular control mechanisms at the level of the microcirculation, as well as the cellular repair mechanisms involved in vascular recovery. Our early findings suggest that pericytes play roles in controlling regional CBF through contractile activity and remodeling the vasculature after trauma-induced BLB damage. The signaling pathways, however, that control the contractile and adaptive activities of pericytes have not been identified. In the brain and retina, "neuro-vascular units" (NVUs), consisting of neurons, astrocytes, pericytes, and smooth muscle, provide direct and swift modulation of local blood flow to match metabolic demand. Cochlear fibrocytes, which resemble astrocytes and glial cells and play a role in recycling K+ from hair cells, are found to be morphologically connected to pericytes on the spiral ligament pre-capillaries. The findings suggest there may be a mechanism analogous to the NVU for regulation of blood flow in the cochlear microcirculation. This proposal, therefore, comprises four Aims to further investigate: 1) the role of fibrocyte-pericyte coupling in the regulation of pericytes and control of CBF; 2) the signaling mechanism of the fibrocyte-pericyte unit; 3) the functional role of fibrocyte-pericyte coupling in bridging between sound activity and CBF; and 4) pericyte recruitment in sound-produced BLB. This study, by providing fundamental knowledge on fibrocyte and pericyte function, will lay the foundation for better clinical management of inner ear disease, prevention of pericyte-related vascular damage, and development of effective clinical treatments for hearing loss. PUBLIC HEALTH RELEVANCE: A wide array of hearing disorders, including sudden sensorineural hearing loss, presbycusis, noise-induced hearing loss, tinnitus, auto-immune hearing loss, and vestibular disorders, involve dysfunction of the blood supply to the cochlea and disruption of the blood-labyrinth barrier (BLB) in the inner ear. It follows that development of new treatments for vascular disorder-related hearing loss will require a better understanding of cochlear blood flow and BLB physiology and pathology. The findings from this study will provide the basis for development of effective medical therapies for inner ear disease.

描述（由申请人提供）：耳蜗微循环对正常听力至关重要，耳蜗血流减少和血迷路屏障（BLB）破坏涉及许多听力障碍。开发血管相关性听力损失的新治疗方法需要更好地了解对耳蜗血流（CBF）的控制和BLB的修复。特别是，我们需要了解微循环水平的局部细胞控制机制，以及血管恢复中涉及的细胞修复机制。我们的早期研究结果表明，周细胞通过收缩活动和重塑创伤诱导的BLB损伤后的血管在控制区域CBF中发挥作用。然而，控制周细胞收缩和适应性活动的信号通路尚未确定。在大脑和视网膜中，由神经元、星形胶质细胞、周细胞和平滑肌组成的“神经血管单位”（NVU）提供对局部血流的直接和迅速的调节以匹配代谢需求。皮质纤维细胞类似于星形胶质细胞和神经胶质细胞，在毛细胞的K+回收中发挥作用，被发现在形态上与螺旋韧带前毛细血管上的周细胞相连。结果表明，可能存在类似于NVU的机制来调节耳蜗微循环中的血流。因此，该提议包括四个目的以进一步研究：1）纤维细胞-周细胞偶联在周细胞的调节和CBF的控制中的作用; 2）纤维细胞-周细胞单元的信号传导机制; 3）纤维细胞-周细胞偶联在声音活动和CBF之间的桥接中的功能作用;以及4）声音产生的BLB中的周细胞募集。本研究通过提供纤维细胞和周细胞功能的基础知识，将为更好地临床管理内耳疾病，预防周细胞相关的血管损伤以及开发有效的听力损失临床治疗方法奠定基础。 公共卫生关系：包括突发性感音神经性听力损失、老年性耳聋、噪声诱发的听力损失、耳鸣、自身免疫性听力损失和前庭障碍在内的广泛的听力障碍涉及耳蜗的血液供应功能障碍和内耳中的血迷路屏障（BLB）的破坏。因此，开发血管疾病相关听力损失的新治疗方法需要更好地了解耳蜗血流和BLB生理学和病理学。这项研究的结果将为开发有效的内耳疾病药物治疗方法提供基础。