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.

项目概要 唾液具有许多极其重要的生物功能，有助于维持口腔 据估计，美国有超过 500 万人患有唾液腺疾病。 唾液分泌功能障碍是由许多离子通道和转运蛋白的协同活动驱动的。 尽管人们认为钙是调节液体分泌的主要细胞内因子，但 参与细胞质钙调节的分子机制尚不清楚。 由于缺乏有关唾液中钙通道调节机制的信息 此外，没有关于胞质钙的增加如何调节唾液的信息。 此外，在干燥综合征患者中，尽管腺泡组织看似正常，但实际上却是正常的。 功能不正常并且对激动剂刺激的钙反应降低。 钙通道可能处于这种病理状态的可能性是从我们获得的结果。 授予的资助表明 TRPC1 是唾液腺中的主要钙通道，并且与唾液腺中的主要钙通道密切相关。 为了了解 TRPC1 通道的调节，我们已经在人类中证明了这一点。 颌下腺细胞，TRPC1 与 STIM1、Cav1 和 Orai1 的相互作用决定了 TRPC1 介导 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。 然而，我们尚不清楚体内唾液腺组织中是否也存在类似的机制。 因此，在本次更新中，我们打算彻底表征胞质钙在唾液腺中的作用 功能并确定瞬时受体电位规范 (TRPC1) -1 和之间的关系 这项研究的假设是，通过 TRPC1 的钙流入在唾液分泌中起着关键作用。 唾液腺的生理功能，唾液腺钙通道的特征将是 了解唾液分泌的机制很重要，唾液分泌可以作为唾液中的药物靶点 我们将协调我们的努力以确定 TRPC1 的功能意义。 我们还将研究调节唾液分泌的通道以及它如何导致唾液腺破坏。 脂筏在小鼠颌下腺细胞 TRPC1 通道组装/激活中的作用 并将确定通过 STIM1 和 Orai1 调节 TRPC1 的机制。 研究有望为钙通道的作用和分子机制提供新的见解 对这些负责唾液分泌的事件有更多的了解。 对于阐明唾液腺功能障碍的新疗法非常重要。