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 唾液执行许多非常重要的生物学功能，这些功能有助于维持口服 健康。据估计，美国有超过500万人患有唾液腺 功能障碍。唾液的分泌是由许多离子频道和转运蛋白的一致活动驱动的。 虽然，人们认为钙是调节流体分泌的主要细胞内因子，即 尚未清楚地了解参与胞质钙调节的分子机制。这是主要的 由于缺乏有关唾液中存在的钙通道调节机制的信息 腺体。此外，没有信息可获得胞质钙如何调节唾液 分泌。此外，在Sjögerns综合征患者中，尽管腺泡组织似乎是正常的 无法正常功能，并且对激动剂刺激的钙反应降低。这种观察提出了 在这种病理状况下，钙通道可能会改变的可能性。从我们的 授予赠款指标，表明TRPC1是唾液网格的主要钙渠道，并且非常紧密 涉及唾液分泌。为了了解TRPC1通道的调节，我们已经表明在人类中 下颌下腺细胞，TRPC1与Stim1，Cav1和Orai1的相互作用决定了TRPC1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结构域 膜，但是，唾液腺组织中体内也存在类似的机制，尚无任何人知道。 因此，在这种续签中，我们打算彻底表征胞质钙在唾液腺中的作用 功能并确定瞬态受体电位规范（TRPC1）-1和 唾液分泌。这项研究的假设是因为通过TRPC1钙影响在 唾液网格的物理功能，唾液网格中钙通道的表征将是 了解唾液分泌的机制很重要，这可以代表唾液中的药物靶标 腺功能障碍。我们将协调我们的努力，以确定TRPC1的功能意义 调节唾液分泌及其如何导致唾液腺破坏的渠道。我们还将调查 脂质筏在小鼠下颌腺细胞中TRPC1通道的组装/激活中的作用 并将通过STIM1和ORAI1确定涉及TRPC1调节的机制。我们的结果 预计研究将为钙通道和分子机制提供新的见解 参与唾液分泌。对这些导致唾液分泌的事件的更多了解将是 对于阐明唾液腺功能障碍的新疗法很重要。