TRPC1, Calcium, and Saliva Secretion

TRPC1、钙和唾液分泌

• 批准号: 8984775
• 负责人: Brij B Singh
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984775
• 关键词: Acinar Cell; Adenoviruses; Adverse effects; 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; Lead; Mastication; Mediating; Membrane Lipids; Membrane Microdomains; Molecular; Mus; Oral; Oral cavity; Oral health; Outcome; 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; Sodium; Speech; Submandibular gland; Syndrome; Taste Perception; Testing; Therapeutic Intervention; Tissues; Work; base; cancer therapy; in vivo; insight; loss of function; mouse model; protein protein interaction; public health relevance; receptor; response; saliva secretion; sensor; soft tissue; symporter; therapeutic target; tool; water channel

 DESCRIPTION (provided by applicant): 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 Sjögren's 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.

 描述（由适用提供）：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腔健康。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。尽管人们认为钙是调节液体分泌的主要细胞内因子，但尚未清楚地理解与胞质钙调节有关的分子机制。这主要是由于缺乏有关唾液网格中存在的钙通道调节机制的信息。此外，没有信息可用，因为唾液分泌的胞质钙调制如何增加。此外，在Sjögren综合征患者中，尽管腺泡组织似乎正常，但它们的功能不正常，并且对激动剂刺激的钙反应下降。该观察结果增加了在这种病理状况下可能改变钙通道的可能性。从我们授予的赠款指标获得的结果表明，TRPC1是唾液网格中的主要钙通道，并且密切涉及唾液分泌。为了了解TRPC1通道的调控，我们表明在人下腺细胞中，TRPC1与STIM1，CAV1和ORAI1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质膜中的特定结构域，但是唾液腺组织中的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功能中的作用，并确定瞬时受体电位规范（TRPC1）-1和唾液分泌之间的关系。这项研究的假设是，因为通过TRPC1通过TRPC1的钙影响在唾液腺的身体功能中起关键作用，因此唾液腺中钙通道的表征对于了解唾液腺的机制至关重要，这可能代表唾液腺功能障碍中的药物靶标。我们将协调我们的努力，以便 确定TRPC1通道在确定唾液分泌及其如何导致唾液腺破坏的功能意义。我们还将研究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识别TRPC1调节所涉及的机制。我们的研究结果有望提供有关钙通道作用以及涉及唾液分泌的分子机制的新见解。对这些负责唾液分泌的事件的更多了解对于阐明唾液烧烤功能障碍的新疗法很重要。