The role of cochlear pericytes in control of cochlear microcirculation

描述（申请人提供）：耳蜗微循环对正常听力至关重要。耳蜗血流量减少与许多听力障碍有关。周细胞是血管周围的微血管，通过对多种血管活性激动剂的反应，在许多器官的微血管血流调节中发挥重要作用。它们还通过合成和分泌基底膜和细胞外基质的结构成分来影响微血管壁的完整性。周细胞生理学及其沿微血管的密度表现出与组织和血管相关的特异性。它们的分布和位置与功能和代谢需求紧密相关。我们以前在耳蜗外侧壁的毛细血管上发现了高密度的周细胞：血管纹和螺旋韧带。我们假设它们通过收缩调节耳蜗微循环。因此，本项目的目的是确定外侧壁周细胞的收缩活动，它们的生理和它们在大声声音引起的内耳血流改变中的参与。在目的1中，我们将在体外诱导和测量周细胞的收缩能力；在第二阶段，我们将在体内诱导和测量周细胞的收缩能力。长期目标是了解耳蜗周细胞相关的信号通路-耳蜗血流调节机制及其参与耳蜗液止血。耳蜗血流量非常小（约为总心输出量的1/ 100万），但对正常听力至关重要。耳蜗血供功能障碍可引起严重的听力障碍，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、耳鸣和某些前庭病变。在临床实践中，血管活性物质一直没有非常有效，因为我们没有对循环的理解。本课题将研究耳蜗微循环的周细胞（平滑肌样细胞，也是产生巨噬细胞、吞噬细胞、成纤维细胞、平滑肌细胞的祖细胞）相关调控机制，深入了解血流调控机制，为内耳疾病的临床医学治疗开发有效的药物。

DESCRIPTION (provided by applicant): The cochlear microcirculation is essential for normal hearing. A reduction of cochlear blood flow is involved in a number of hearing disorders. Pericytes, surrounding blood microvessels, play important roles for many organs in the regulation of microvessel blood flow by responding to a wide variety of vasoactive agonists. They also affect the microvessel wall integrity by synthesizing and secreting structural constituents of the basement membrane and extracellular matrix. Pericyte physiology and their density along the microvessels exhibit tissue-related and vessel-related specificity. Their distribution and locations are tightly coupled to functional and metabolic needs. We have previously found a high density of pericytes on the capillaries of the cochlear lateral wall: in the stria vascularis and spiral ligament. We hypothesize that they regulate cochlear microcirculation through their contraction. Therefore, the goals of this project are to determine the contractile activity of lateral wall pericytes, their physiology and their involvement in the loud sound induced inner ear blood flow alteration. In Aim 1, we will induce and measure pericyte contractility in vitro; In Aim 2, we will induce and measure pericyte contractility in vivo. A long-term goal is to understand cochlear signaling pathways of pericyte related-regulatory mechanisms in cochlear blood flow and their involvement in cochlear fluid hemostasis. The volume of cochlear blood flow is extremely small (on the order of 1/1 000 000 of total cardiac output), yet critically important for normal hearing. Dysfunctions in the cochlear blood supply can cause serious hearing disorders including sudden sensorineural hearing loss, presbyacusis, noise-induced hearing loss, tinnitus, and certain vestibulopathies. In clinical practice vasoactive substances have been have not been very effective because we do not have an understanding of the circulation. In this research project, we will investigate the pericyte (smooth muscle-like cells and also a progenitor cell to generate macrophages and phagocytes, fibroblasts, and smooth muscle cells) related regulatory mechanisms of cochlear microcirculation and gain a deeper understanding of the mechanisms that control of blood flow in order to develop effective clinical medical therapies for inner ear disease.