The role of cochlear pericytes in control of cochlear microcirculation

描述(申请人提供)：耳蜗微循环是正常听力所必需的。耳蜗血流量减少与许多听力障碍有关。周细胞是周围血管微血管周围的细胞，通过对多种血管活性激动剂的反应，对许多器官的微血管血流调节起着重要作用。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组织相关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密切相关。我们以前在耳蜗侧壁的毛细血管：血管纹和螺旋韧带中发现了高密度的周细胞。我们假设它们通过收缩来调节耳蜗微循环。因此，本项目的目标是确定侧壁周细胞的收缩活动及其生理机制，以及它们在大声音引起的内耳血流改变中的作用。在目标1中，我们将在体外诱导并测量周细胞的收缩性能；在目标2中，我们将在体内诱导并测量周细胞的收缩性能。一个长期的目标是了解耳蜗周细胞相关的信号通路在耳蜗血流量中的调节机制及其在耳蜗液止血中的作用。耳蜗血流量极小(约为心输出量的1/100万)，但对正常听力至关重要。耳蜗血供障碍可导致严重的听力障碍，包括突发性感音神经性听力损失、老年性聋、噪声性听力损失、耳鸣和某些前庭疾病。在临床实践中，血管活性物质一直不是很有效，因为我们对循环没有了解。在本研究项目中，我们将研究周细胞(平滑肌样细胞，也是产生巨噬细胞和吞噬细胞、成纤维细胞和平滑肌细胞的前体细胞)对耳蜗微循环的相关调控机制，以更深入地了解调控血流的机制，以期为内耳疾病的临床治疗提供有效的药物治疗方法。

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.