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（由申请人提供）：唾液腺腺泡细胞与唾液蛋白和液体分泌高水平的钙。然后，这种唾液会向下行驶导管系统，直到到达口腔。唾液导管具有最低的分泌功能，并被认为参与了Na+等离子的重吸收。目前尚不清楚唾液腺管道是否像外分泌胰管一样；重新吸收钙，因为唾液中的[Ca2+]很高。一些较早的报道表明，唾液中的[Ca2+]逐渐减少，而导管管道则流动。因此，我们提出唾液导管细胞可能会重新吸收Ca2+，因为维持钙水平对于维持通过导管管腔的唾液流量至关重要。此外，高唾液钙被认为是导致唾液腺结石形成或唾液石的促成因素。唾液导管中的石材形成是最常见的唾液腺疾病，是由于钙浓度较高而主要由磷酸钙组成的唾液结石引起的。重要的是要注意，在肾脏等组织中，石材的形成与钙重吸收的变化有关。尚不清楚通过唾液腺管通过调节钙水平的调节钙的钙吸收是否尚不清楚。 TRPC3，Ca2+进入通道主要位于SMG管道中的顶膜中。 CSR，G蛋白偶联受体也存在于同一唾液腺管道中，它似乎与TRPC3相关。我们的中心假设是，从腺泡细胞分泌的唾液中的钙在流经导管系统时激活了CSR，该系统可能通过TRPC3通道调节Ca2+流入。这将导致跨唾液导管细胞跨钙钙通量。我们建议这种调节唾液钙浓度可保护唾液导管免受钙石的形成。这项研究涉及唾液腺功能的尚未知道的方面，即钙的重吸收。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，这些发现还将揭示唾液腺是否具有固有的自动调节机制，从而可以防止因导管障碍物引起的唾液腺功能障碍。因此，我们认为我们的概念具有创新性，拟议的研究是新颖的。从这项研究中获得的信息不仅将有助于理解导管细胞功能的基本方面，而且还将揭示涉及唾液石症的机制，这些机制可能可能应用于治疗策略的发展。未来方向：目前的研究将有助于了解TRPC3在Ca2+进入唾液导管细胞中的作用。这种Ca2+流入可能是唾液导管细胞中Ca2+重吸收的机制。根据从这项研究中获得的结果，我们将建立一个更大的项目，以了解钙石材形成发展的细胞和分子基础，这将非常有帮助，这对预防唾液石症非常有帮助。此外，这项研究和未来项目还将有助于确定为上述临床状况开发新药物的潜在候选者。 公共卫生相关性：唾液线虫病，由于唾液管阻塞而导致唾液管的石材形成是最常见的唾液腺疾病。据估计，它会影响1000名成人人群中的12个，占大型唾液腺疾病的50％以上。目前的研究将有助于理解可能应用于治疗策略的开发中所涉及的唾液石症的机制。这项研究非常重要，因为高唾液钙被认为是唾液石形成的一个促成因素。这项研究还解决了唾液腺功能的尚未清楚的方面，即钙的重吸收。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。