Fibrovascular coupling in the cochlea and pericyte recruitment after noise

描述(申请人提供)：耳蜗微循环对正常听力是必不可少的，耳蜗血流量减少和血迷路屏障(BLB)破坏与许多听力障碍有关。血管相关性听力损失的新治疗方法的发展需要更好地了解对耳蜗血流量的控制和对耳蜗血流量的修复。特别是，我们需要了解微循环水平上的局部细胞调控机制，以及参与血管恢复的细胞修复机制。我们早期的研究结果表明，周细胞通过收缩活动和重塑创伤诱导的血脑屏障损伤后的血管系统，在控制局部脑血流中发挥作用。然而，控制周细胞收缩和适应活动的信号通路尚未确定。在大脑和视网膜中，“神经血管单位”(NVU)由神经元、星形胶质细胞、周细胞和平滑肌组成，为局部血流提供直接和快速的调节，以满足代谢需求。耳蜗纤维细胞类似于星形胶质细胞和胶质细胞，在毛细胞回收K+的过程中起作用，在形态上与螺旋韧带前毛细血管上的周细胞相连。这一发现表明，可能存在一种类似于NVU的机制来调节耳蜗微循环中的血流。因此，这一建议包括四个进一步研究的目的：1)纤维细胞-周细胞偶联在调控周细胞和CBF中的作用；2)纤维细胞-周细胞单位的信号机制；3)纤维细胞-周细胞偶联在声音活动和CBF之间的桥梁作用；以及4)周细胞在声音产生的BLB中的募集。本研究通过提供有关纤维细胞和周细胞功能的基础知识，将为更好地临床治疗内耳疾病、预防周细胞相关血管损伤以及开发有效的临床听力损失治疗方法奠定基础。 与公共卫生相关：广泛的听力障碍，包括突发性感音神经性听力损失、老年性耳聋、噪声性听力损失、耳鸣、自身免疫性听力损失和前庭疾病，涉及耳蜗血供障碍和内耳血迷路屏障(BLB)的破坏。因此，血管疾病相关听力损失的新治疗方法的开发将需要更好地了解耳蜗血流量和BLB的生理学和病理学。这项研究的结果将为开发有效的内耳疾病治疗方法提供依据。

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.