Function of TRPC3 in salivary gland

TRPC3在唾液腺中的功能

• 批准号: 7789983
• 负责人: Bidhan Chandra Bandyopadhyay
• 金额: $ 6.32万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789983
• 关键词: Accounting; Acinar Cell; Address; Adenovirus Vector; Adult; Affect; Agonist; Biochemical; Biotinylation; Calcium; Calcium-Sensing Receptors; Calculi; Cell Line; Cell membrane; Cell physiology; Cell surface; Cells; Clinical; Co-Immunoprecipitations; Complex; Data; Deposition; Development; Disease; Duct (organ) structure; Ductal; Ductal Epithelial Cell; Ductal Epithelium; Epithelium; Exocrine pancreas; Figs - dietary; Functional disorder; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Goals; Ion Channel; Ions; Kidney Calculi; Knockout Mice; Liquid substance; Little' s Disease; Luminal region; MDCK cell; Maintenance; Measures; Mediating; Membrane; Molecular; Molecular Genetics; Mus; Obstruction; Oral cavity; Pancreatic duct; Pb in saliva; Pharmaceutical Preparations; Phenotype; Physiology; Population; Regulation; Reporting; Research; Research Personnel; Role; Saliva; Salivary; Salivary Calculi; Salivary Duct Calculi; Salivary Gland Diseases; Salivary Glands; Salivary Proteins; Salivary duct structure; Sialolithiasis; Signal Transduction; Submandibular gland; System; TRP channel; Testing; Tissues; Transactivation; Travel; Vanilloid; apical membrane; base; calcium phosphate; extracellular; innovation; luminal membrane; monolayer; novel; overexpression; prevent; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; research study; response; saliva secretion; therapeutic development

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.

描述(申请人提供)：唾液腺腺泡细胞分泌高水平的钙以及唾液蛋白和液体。然后这种唾液沿着导管系统流下，直到到达口腔。唾液导管具有最小的分泌功能，被认为参与了对Na+等离子的重吸收。目前尚不清楚唾液腺导管是否像外分泌胰腺导管一样重新吸收钙，因为唾液中的[Ca~(2+)]很高。早期的一些报道表明，流经导管管腔时，唾液中的钙离子浓度有一个梯度的下降。因此，我们认为唾液导管细胞可能会重新吸收钙离子，因为维持钙水平对于维持唾液流经导管管腔是必不可少的。此外，高唾液钙被认为是唾液腺结石形成或涎石形成的一个促成因素。涎管结石是唾液腺最常见的疾病，它是由于高浓度钙的存在而形成以磷酸钙为主的唾液结石而引起的。值得注意的是，在肾脏等组织中，结石的形成与钙重新吸收的变化有关。目前尚不清楚通过唾液腺导管进行的钙重吸收是否参与调节唾液中的钙水平。TRPC3是一种钙离子进入通道，主要定位于SMG导管的顶膜。CSR是一种G蛋白偶联受体，也存在于唾液腺导管的同一区域，在那里它似乎与TRPC3有关。我们的中心假设是，腺泡细胞分泌的唾液中的钙激活了CSR，同时流经导管系统，这可能通过TRPC3通道调节钙离子的内流。这将导致跨越涎腺导管细胞的跨上皮钙流。我们认为，这种对唾液钙浓度的调节有助于保护唾液管免受钙结石的形成。这项研究涉及唾液腺功能的一个未知方面，即钙的重新吸收。此外，从拟议的研究中获得的数据将阐明唾液导管是否积极参与调节唾液质量。最后，这些发现还将揭示唾液腺是否具有内在的自我调节机制，这种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，我们相信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，而且还将揭示涎石症的相关机制，这些机制可能会应用于治疗策略的开发。未来方向：目前的研究将有助于了解TRPC3在钙离子进入涎腺导管细胞中的作用。这种钙内流可能是涎腺导管细胞重吸收钙的一种机制。基于这项研究的结果，我们将建立一个更大的项目，以了解钙结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针对上述临床疾病开发新药的潜在候选者。 公共卫生背景：涎石症是唾液腺最常见的疾病，因唾液管阻塞而在唾液管内形成结石。据估计，每1000名成年人口中就有12人感染这种疾病，占大唾液腺疾病的50%以上。本研究将有助于了解涎石症的发病机制，并有可能应用于治疗策略的开发。这项研究非常重要，因为高唾液钙被认为是唾液结石形成的一个促成因素。这项研究还涉及唾液腺功能的一个未知方面，即钙的重新吸收。此外，这项拟议的研究将阐明唾液导管是否积极参与调节唾液质量。