Cellular electrophysiology of vasculatures in inner ear

描述（由申请人提供）：强有力的证据表明，血液循环障碍会导致大声声音引起的创伤、衰老、梅尼埃病、耳毒性药物和某些形式的突发性耳聋的听力损失。要了解和治疗这些听力疾病，内耳血管生理学的知识是先决条件。耳蜗血管的调节机制尚不清楚。这项建议的长期目标是增加我们对这些血管的细胞和亚细胞生理学的理解，以及它们与其他血管床的血管有何不同。具体而言，本研究旨在：1)确定导致耳蜗螺旋小臼齿动脉（SMA）平滑肌细胞两种不同水平静息电位的膜通道和机制；2)确定候选神经递质和神经肽对离子通道、相关受体和细胞内信号通路的作用；3)识别SMA中神经肌肉传递的性质；4)确定SMA与脑和肠小动脉的收缩和细胞特性有何不同。这些目标将通过常规和全细胞电流和电压钳记录方法在SMA片段的体外平滑肌细胞上进行实验，以及单细胞标记和血管加压素测量来实现。将对SMA与脑和肠小动脉之间的收缩和膜特性进行比较研究，以评估血管床之间的异质性。通过这些研究，我们期望描述独特的收缩和膜特性，关键离子通道特征，功能性神经肌肉递质和相关受体，以及这些功能特性在SMA中调节的机制；此外，我们希望了解SMA的这些机制与其他血管床的机制有何不同。所获得的知识将提高我们对耳蜗血流如何被独特调节的理解，从而有助于理解循环相关听力损失，并导致这些听力状况的预防和治疗。所获得的知识在心血管生理学的广泛领域也应具有重要意义。

DESCRIPTION (provided by applicant): Strong evidence suggests that blood circulation disturbances contribute to hearing losses in loud sound induced trauma, aging, Meniere's disease, ototoxic drugs and some forms of sudden deafness. To understand and treat these hearing conditions, knowledge of inner ear vascular physiology is a prerequisite. Little is known about the regulating mechanisms of cochlear vessels. The long-term objective of this proposal is to increase our understanding of the cellular and subcellular physiology of these vessels and how they differ from vessels of other vascular beds. Specifically, this proposal aims to: 1) determine the membrane channels and mechanisms that cause two distinct levels of resting potentials in smooth muscle cells of cochlear spiral modiolar artery (SMA); 2) determine the actions of candidate neurotransmitters and neuropeptides on the ion channels, the responsible receptors and the intracellular signaling pathways; 3) identify the nature of neuromuscular transmission in the SMA; 4) determine how the contractile and cellular properties of the SMA differ from small arteries of the brain and intestine. These goals will be achieved by experiments using conventional and whole-cell current- and voltage-clamp recording methods on in vitro smooth muscle cells in segments of the SMA, as well as single-cell labeling and vasotone measurements. Comparative studies of contractile and membrane properties between the SMA and the arterioles from the brain and intestine will be conducted to evaluate the heterogeneity among the vessel beds. With these studies, we expect to describe the unique contractile and membrane properties, key ionchannel features, functional neuromuscular transmitters and related receptors, and mechanisms by which these functioning properties are regulated in the SMA; in addition, we expect to understand how these mechanisms of the SMA differ from those of other vessel beds. The knowledge obtained will improve our understanding of how cochlear blood flow is uniquely regulated, thus contributing to the understanding of circulation-related hearing losses and leading to prevention and treatment of these hearing conditions. The acquired knowledge should also be of significance in broad areas of cardiovascular physiology.