Function of TRPC3 in salivary gland

描述（由申请方提供）：唾液腺腺泡细胞分泌高水平的钙以及唾液蛋白和液体。然后，这些唾液沿着导管系统向下行进，直到它到达口腔。唾液管具有最小的分泌功能，并且被认为参与离子（例如Na+）的重吸收。目前尚不清楚唾液腺导管是否像外分泌胰腺导管一样重吸收钙，因为唾液中的[Ca 2 +]很高。一些早期的报道显示，当唾液流过导管腔时，唾液中的[Ca 2 +]存在梯度降低。因此，我们建议，唾液导管细胞可能会重吸收钙离子，因为维持钙水平是必不可少的维持唾液流通过导管腔。此外，高唾液钙已被认为是唾液腺结石形成或涎石的一个促成因素。唾液管结石形成是唾液腺最常见的疾病，其由唾液结石的形成引起，所述唾液结石主要由由于存在较高浓度的钙而导致的磷酸钙组成。值得注意的是，在肾脏等组织中，结石形成与钙重吸收的变化有关。唾液腺导管对钙的重吸收是否参与调节唾液中的钙水平尚不清楚。TRPC 3是一种主要定位于SMG导管顶膜的Ca 2+进入通道。CSR是一种G蛋白偶联受体，也存在于唾液腺导管的相同区域，在那里它似乎与TRPC 3相关。我们的中心假设是腺泡细胞分泌的唾液中的钙激活CSR，同时流过导管系统，可能通过TRPC 3通道调节Ca 2+内流。这将导致跨上皮钙流通过唾液导管细胞。我们认为这种调节唾液钙浓度的作用是保护唾液导管免受钙结石的形成。这项研究解决了唾液腺功能的一个未知方面，即钙重吸收。此外，从拟议的研究中获得的数据将阐明唾液管是否积极参与调节唾液的质量。最后，研究结果还将揭示唾液腺是否具有固有的自动调节机制，可以防止由于导管阻塞而导致的唾液腺功能障碍。因此，我们认为我们的概念是创新的，所提出的研究是新颖的。从这项研究中获得的信息不仅有助于了解导管细胞功能的基本方面，而且还将揭示参与涎石病的机制，这些机制可能适用于治疗策略的开发。未来研究方向：本研究将有助于了解TRPC 3在钙离子进入唾液导管细胞中的作用。这种Ca ~（2+）内流可能是唾液腺导管细胞Ca ~（2+）重吸收的一种机制。基于本研究的结果，我们将建立一个更大的项目，以了解钙石形成的细胞和分子基础，这将对预防涎石症非常有帮助。此外，这项研究和未来的项目也将有助于确定潜在的候选人，以开发用于上述临床病症的新药。 公共卫生相关性：涎石症是涎腺最常见的疾病，是由于涎腺导管阻塞而在涎腺导管内形成结石。据估计，每1000名成年人中就有12人患有此病，占大唾液腺疾病的50%以上。目前的研究将有助于了解参与涎石症的机制，可能会在治疗策略的发展应用。这项研究是非常重要的，因为高唾液钙已被认为是一个促成因素的涎石的形成。这项研究还涉及唾液腺功能的一个未知方面，即钙重吸收。此外，拟议的研究将阐明唾液管是否积极参与调节唾液的质量。

DESCRIPTION (provided by applicant): Salivary gland acinar cells secrete high levels of calcium together with salivary proteins and fluids. This saliva then travels down the ductal system till it reaches the oral cavity. Salivary ducts have minimal secretory function and are proposed to be involved in reabsorption of ions such as Na+. It is presently unclear whether salivary gland ducts, like exocrine pancreatic ducts; reabsorb calcium since [Ca2+] in saliva is high. Some earlier reports show that there is a gradient in decrease in [Ca2+] in the saliva while flowing though the ductal lumen. Therefore we propose that salivary ductal cells might reabsorb Ca2+ since maintaining the calcium levels is essential for the maintenance of salivary flow through the ductal lumen. Furthermore, high saliva calcium has been suggested to be a contributing factor to the salivary gland stone formation or sialoliths. Stone formation in salivary duct is the most common disease of salivary glands that is caused by the formation of salivary calculi consisting of mainly calcium phosphate due to the presence of higher concentration of calcium. It is important to note that in tissues such as kidney, stone formation is associated with changes in calcium reabsorption. Whether calcium reabsorption via salivary gland ducts is involved in modulating calcium levels in saliva is not yet known. TRPC3, a Ca2+ entry channel is predominantly localized in apical membrane in the ducts of the SMG. CSR, a G-protein coupled receptor is also present in the same region of salivary gland ducts where it appears to associate with TRPC3. Our central hypothesis is that calcium in saliva secreted from acinar cells activates the CSR while flowing through the ductal system that potentially modulate the Ca2+ influx via TRPC3 channel. This would result in transepithelial calcium flux across the salivary ductal cell. We suggest that such regulation of saliva calcium concentration serve to protect salivary duct from calcium stone formation. This research addresses an as yet unknown aspect of salivary gland function, i.e. calcium reabsorption. Furthermore, data obtained from the proposed study will elucidate whether salivary ducts are actively involved in regulating the quality of saliva. Finally, the findings will also reveal whether salivary glands have inherent autoregulatory mechanisms, which prevent salivary gland dysfunction due to ductal obstructions. Thus we believe our concept is innovative and the proposed research is novel. Information gained from this study will not only help understanding basic aspects of ductal cell function but will also reveal mechanisms involved in sialolithiasis that could be potentially applied in development of therapeutic strategies. Future direction: Present study will help to understand the role of TRPC3 in Ca2+ entry into the salivary ductal cells. This Ca2+ influx could be a mechanism of Ca2+ reabsorption in salivary ductal cells. Based on the results obtained from this study, we will build up a bigger project to understand the cellular and molecular basis of the development of calcium stone formation and this will be extremely helpful to prevent sialolithiasis. Furthermore, this study and the future project will also help to identify the potential candidates to develop new drugs for the above clinical condition. Public Health Relevance: Sialolithiasis, stone formation in salivary duct due to blockage of salivary duct is the most common disease of salivary glands. It is estimated to affect 12 in 1000 of the adult population and accounts for more than 50% of diseases of the large salivary glands. Present study will help to understand the mechanisms involved in sialolithiasis that could be potentially applied in development of therapeutic strategies. This research is very important since high saliva calcium has been suggested to be a contributing factor to the formation of sialoliths. This research also addresses an as yet unknown aspect of salivary gland function, i.e. calcium reabsorption. Additionally, the proposed study will elucidate whether salivary ducts are actively involved in regulating the quality of saliva.