TRPC1, Calcium, and Saliva Secretion

TRPC1、钙和唾液分泌

• 批准号: 9900137
• 负责人: Brij B Singh
• 金额: $ 1.61万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900137
• 关键词: Acinar Cell; Adenoviruses; Adverse drug effect; Affect; Agonist; Autoimmune Diseases; Award; Biological Process; Calcium; Calcium Channel; Carrier Proteins; Cell Death; Cell Line; Cell membrane; Cells; Chloride Channels; Complex; Data; Deglutition; Disease; Drug Targeting; Etiology; Event; Excision; Fluids and Secretions; Functional disorder; Funding; Goals; Grant; Head and Neck Cancer; Human; Immune; Infiltration; Intervention; Ion Channel; Knockout Mice; Lead; Mastication; Mediating; Membrane Microdomains; Molecular; Mus; Oral; Oral cavity; Oral health; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Play; Population; Positioning Attribute; Potassium Channel; Potassium Chloride; Proteins; Publishing; Radiation therapy; Regulation; Research; Role; STIM1 gene; Saliva; Salivary Gland Diseases; Salivary Gland Tissue; Salivary Glands; Sampling; Signal Transduction; Sjogren' s Syndrome; Small Interfering RNA; Sodium; Speech; Submandibular gland; Syndrome; Taste Perception; Testing; Therapeutic Intervention; Tissues; base; cancer therapy; in vivo; insight; mouse model; novel therapeutics; protein protein interaction; receptor; response; saliva secretion; sensor; side effect; soft tissue; symporter; targeted treatment; tool; water channel

Project Summary Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral health. It has been estimated that more than 5 million people in the US suffers from salivary gland dysfunction. Secretion of saliva is driven by concerted activities of a number of ion channels and transporters. Although, it is believed that calcium is the primary intracellular factor that regulates fluid secretion, the molecular mechanism involved in the regulation of cytosolic calcium is not clearly understood. This is primarily due to the lack of information regarding the mechanism of regulation of calcium channels present in salivary glands. Furthermore, no information is available as how increase in cytosolic calcium modulates saliva secretion. Moreover, in Sjögerns 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. Results obtained from our awarded grant indicate that TRPC1 is the primary calcium channel in salivary glands and is intimately involved saliva secretion. To understand the regulation of TRPC1 channel we have shown that in human submandibular gland cells, TRPC1 interaction with STIM1, Cav1, and Orai1 dictates TRPC1 mediated calcium entry. Furthermore, these protein-protein interactions were confined to specific domains in the plasma membrane, however nothing is known if similar mechanisms are also present in vivo in salivary gland tissues. Therefore, in this renewal we intend to thoroughly characterize the role of cytosolic calcium in salivary gland function and to determine the relationship between transient receptor potential canonical (TRPC1) -1 and saliva secretion. The hypothesis of this study is that because calcium influx via TRPC1 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 in regulating saliva secretion and how it leads to salivary gland destruction. We will also investigate the role of lipid rafts in the assembly/activation of the TRPC1 channel in mouse submandibular gland cells and will identify the mechanism involved in the regulation of TRPC1 via STIM1 and Orai1. 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 dysfunctions.

项目摘要 唾液执行许多极其重要的生物功能，这些功能有助于维持口腔健康。 健康据估计，美国有超过500万人患有唾液腺疾病。 功能障碍唾液的分泌由许多离子通道和转运蛋白的协同活动驱动。 尽管认为钙是调节液体分泌的主要细胞内因子， 涉及胞质钙调节的分子机制尚不清楚。这主要是 由于缺乏关于唾液中存在的钙通道调节机制的信息， 腺体此外，没有关于细胞溶质钙的增加如何调节唾液的信息 分泌物此外，在干燥综合征患者中，虽然腺泡组织看起来正常，但它们确实 不能正常发挥功能，并且对激动剂刺激的钙反应降低。这一观察提出了 在这种病理状态下钙通道可能发生改变的可能性。结果从我们的 授予基金表明TRPC 1是唾液腺中主要钙通道， 涉及唾液分泌。为了了解TRPC 1通道的调节，我们已经表明，在人类中， 下颌下腺细胞，TRPC 1与STIM 1，Cav 1和Orai 1的相互作用决定TRPC 1介导的 钙进入此外，这些蛋白质-蛋白质相互作用仅限于血浆中的特定区域 膜，然而，如果类似的机制也存在于唾液腺组织中，则一无所知。 因此，在这次更新中，我们打算彻底描述唾液腺细胞内钙离子的作用 功能，并确定瞬时受体电位典型（TRPC 1）-1和 唾液分泌这项研究的假设是，由于通过TRPC 1的钙内流在 唾液腺的生理功能，唾液腺中钙通道的表征将是 因此，了解唾液分泌的机制是非常重要的，这可能是唾液中的药物靶点。 腺体功能障碍我们将协调我们的努力，以确定TRPC 1的功能意义 通道调节唾液分泌和它如何导致唾液腺破坏。我们亦会研究 脂筏在小鼠颌下腺细胞TRPC 1通道组装/激活中的作用 并将通过STIM 1和Orai 1确定TRPC 1调节的机制。的成果 这些研究有望为钙通道的作用及其分子机制提供新的见解。 参与唾液分泌。更好地了解这些事件负责唾液分泌将 在阐明唾液腺功能障碍的新疗法中具有重要意义。