TRPC1 and saliva secretion

描述（由申请人提供）：唾液具有许多极其重要的生物功能，有助于维持口腔健康。据估计，美国有超过200万人受到唾液腺功能障碍的影响。唾液的分泌由许多离子通道和转运蛋白的协同活动驱动。虽然钙是调节体液分泌的主要细胞内因子，但对调节胞质钙的分子机制还不清楚。这主要是由于缺乏关于唾液腺中存在的钙通道的信息。此外，在干燥综合征患者中，虽然腺泡组织似乎是正常的，但它们不能正常发挥功能，并且对激动剂刺激的钙反应降低。这一观察结果提出了在这种病理条件下钙通道可能改变的可能性。瞬时受体电位（TRP）超家族的成员已被确定为钙通道，这可能是重要的激动剂刺激的液体分泌。因此，本研究旨在彻底表征细胞溶质钙在唾液腺功能中的作用，并确定瞬时受体电位（TRPC 1）蛋白-1和唾液分泌之间的关系。我们的初步数据表明，TRP蛋白在唾液腺中表达，并参与唾液分泌。本研究的假设是，由于钙在唾液腺的生理功能中起着关键作用，唾液腺中钙通道的表征对于理解唾液分泌机制将是重要的，这可能代表唾液腺功能障碍的药物靶点。我们将协调我们的努力，以确定TRPC 1通道蛋白的功能意义，通过使用TRPC 1基因敲除小鼠检测其基因破坏的效果。目的二：研究TRPC 1蛋白在小鼠下颌下腺细胞中的定位和生物化学特性。目的3：研究TRPC 1蛋白的调控机制。我们的研究结果有望为钙通道的作用和参与唾液分泌的分子机制提供新的见解。更好地了解这些事件负责唾液分泌将是重要的，阐明新的治疗唾液腺功能障碍。

DESCRIPTION (provided by applicant): Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral health. It has been estimated that more than 2 million people in the U.S. is compromised by from salivary gland dysfunction. Secretion of saliva is driven by concerted activities of a number of ion channels and transporters. Although, it is well established that calcium is the primary intracellular factor which regulates fluid secretion, the molecular mechanism involved in the regulation of cytosolic calcium is not clearly understood. This is primarily due to the absence of information regarding the calcium channels present in salivary glands. Moreover, in Sjogren's syndrome patients, although the acinar tissues appear to be normal, they do not function properly and have a decreased calcium response to agonist-stimulation. This observation raises the possibility that calcium channels might be altered in this pathological condition. Members of the Transient Receptor Potential (TRP) superfamily have been identified as calcium channels, which could be important in agonist-stimulated fluid secretion. Therefore, this study is designed to thoroughly characterize the role of cytosolic calcium in salivary gland function and to determine the relationship between transient receptor potential (TRPC1) protein-1 and saliva secretion. Our preliminary data indicates that TRP proteins are expressed in salivary glands and are involved in salivary secretion. The hypothesis of this study is that since calcium plays a pivotal role in the physiological function of salivary glands, characterization of calcium channels in salivary glands will be important to understand the mechanism of saliva secretion, which could represent as drug targets in salivary gland dysfunction. We will coordinate our efforts in order to determine the functional significance of TRPC1 channel protein by examining its effect by gene disruption using TRPC1 knockout mice. In Aim 2, we will investigate the localization and biochemical characterization of TRPC1 protein in mouse submandibular gland cells. Aim 3 will identify the mechanism involved in the regulation of TRPC1 protein. The results of our studies are expected to provide new insights into the role of calcium channels and the molecular mechanism involved in saliva secretion. Greater understanding of these events responsible for saliva secretion will be important in elucidating new therapy for salivary gland dysfunction.