Fibrovascular coupling in the cochlea and pericyte recruitment after noise

描述（由申请人提供）：耳蜗微循环对正常听力至关重要，耳蜗血流量减少和血迷宫屏障（BLB）破坏涉及许多听力障碍。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耳蜗血流量（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，以及参与血管恢复的细胞修复机制。我们的早期研究结果表明，周细胞在创伤性BLB损伤后通过收缩活动和重塑血管系统来控制区域CBF。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，“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，提供直接和快速的局部血流调节，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，在毛细胞的K+循环中起作用，被发现在形态上与螺旋韧带前毛细血管上的周细胞相连。研究结果表明，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，本研究包括以下四个方面：1)纤维细胞-周细胞偶联在周细胞调节和CBF控制中的作用；2)纤维细胞-周细胞单位的信号传导机制；3)纤维细胞-周细胞偶联在声音活动和脑血流之间的桥接中的功能作用；4)发声BLB的周细胞募集。本研究通过对纤维细胞和周细胞功能的基础认识，为更好地临床管理内耳疾病，预防周细胞相关血管损伤，制定有效的听力损失临床治疗方法奠定基础。

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.