Fluid Secretion in Parotid Cells: Signal Transduction

腮腺细胞的液体分泌：信号转导

基本信息

批准号：
7575113
负责人：
Stephen Paul Soltoff
金额：
$ 40.77万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-05-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575113
关键词：
1,2-diacylglycerol Acinar Cell Address Adrenergic Receptor Affect Area Biochemistry Biological Models Carbachol Cations Cell Line Cell physiology Cells Cellular biology Communication Coupling Deglutition Dental caries Diglycerides Disease Electrolytes Event Exhibits Exocrine System Fluids and Secretions Functional disorder Future G-Protein-Coupled Receptors Gland Goals Heterotrimeric GTP-Binding Proteins Hydrolysis Individual Investigation Ion Channel Ion Transport Ions Ligands Link Liquid substance MAPK3 gene Mediating Metabolism Mitochondria Modeling Molecular Muscarinic M3 Receptor Mycoses Na(+)-K(+)-Exchanging ATPase Neurotransmitters Oral health Ouabain Parotid Gland Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipase C Phosphorylation Phosphotransferases Physiological Process Protein Kinase Protein Secretion Quality of life Regulation Research Research Personnel Risk Saliva Salivary Salivary Glands Scheme Signal Transduction Signaling Protein Sjogren&apos s Syndrome Substance P Receptor Taste Perception Techniques base experience immortalized cell inhibitor/antagonist interest oral fungal parotid cell programs protein activation receptor receptor binding sensor transport inhibitor

项目摘要

DESCRIPTION (provided by applicant): The broad long-range goal of this research is to understand on a molecular level the mechanisms by which neurotransmitters promote receptor-mediated increases in saliva formation (fluid and electrolyte secretion) in parotid acinar cells. Salivary dysfunction and salivary diseases (including Sjogren's Syndrome) present significant oral health concerns as well as quality of life issues. Clinically, individuals experiencing salivary gland hypofunction (reduced salivary flow rates) have difficulty in swallowing, increased risks of dental caries and oral fungal infections, and alterations in taste. Thoughtful consideration of these problems and how to treat them necessitates a full understanding of fluid and protein secretion by salivary glands. Parotid cells and salivary glands have served as model systems to explore the coupling between signaling events and the initiation of secretion. The overall sequence of events of receptor binding, phospholipase C activation, [Ca2+]i elevation, and the opening of Ca2+-sensitive ion channels has been well characterized. Although this sequence serves as a template for the initiation of secretion in salivary and other exocrine cells, recent research has provided a much more detailed scheme of the events involved in secretion at multiple levels within this overall scheme. This proposal originates from several of our observation relating to cell metabolism, ion transport, and the activation of cell signaling proteins. Several experimental results indicate that AMP-dependent protein kinase (AMPK) activation affects multiple parotid signaling and functional processes, and that ERK1/2 and the Na,K-ATPase exhibit a bi-directional communication. To gain a more complete understanding of parotid acinar cell function, we propose the following interrelated Specific Aims: Aim 1 is to determine the molecular details of the bi-directional signaling between the Na,K-ATPase and ERK1/2. Aim 2 is to determine if the alpha-1 subunit of the Na,K-ATPase is phosphorylated by kinases in carbachol-treated parotid acinar cells. Aim 3 is to examine the contribution of ERK1/2 and changes in intracellular Na to the Na,K-ATPase activity in CIO cells, an immortalized parotid acinar cell line. We will use electrophysiological techniques to resolve questions that we are unable to address using native parotid cells. Aim 4 is to examine regulatory changes in parotid acinar cell signaling and function when intracellular ATP is reduced. Aim 5 is to determine the involvement of AMPK in parotid cell signaling and function. AMPK is activated in an ouabain-dependent manner by receptor ligands that increase the Na,K-ATPase activity. We suggest that these areas of investigation will provide a more complete understanding of parotid cell function, and thereby contribute to future therapies to aid salivary dysfunction.

描述（由申请人提供）：这项研究的广泛远程目标是在分子水平上了解神经递质促进受体介导的唾液形成（液体和电解质分泌）的机制。唾液功能障碍和唾液疾病（包括Sjogren综合症）表现出重大的口腔健康问题以及生活质量问题。在临床上，患有唾液腺功能低下（唾液流量降低）的个体在吞咽，龋齿和口服真菌感染的风险增加以及味道改变方面困难。对这些问题以及如何治疗这些问题进行周到的考虑，需要对唾液腺充分了解液体和蛋白质分泌。腮腺细胞和唾液腺已成为模型系统，以探索信号事件与分泌的开始之间的耦合。受体结合，磷脂酶C激活，[Ca2+] I升高以及Ca2+敏感离子通道的开放的总体序列已得到很好的特征。尽管该序列是启动唾液和其他外分泌细胞分泌的模板，但最近的研究提供了一个更详细的方案，即该整体方案中多个级别的分泌事件涉及的事件。该建议源自我们的几种观察结果，该观察结果与细胞代谢，离子转运和细胞信号蛋白的激活有关。几个实验结果表明，AMP依赖性蛋白激酶（AMPK）激活会影响多个腮腺信号传导和功能过程，并且ERK1/2和Na，K-ATPase表现出双向通信。为了更完整地了解腮腺细胞功能，我们提出以下相互关联的特定目的：目标1是确定Na，K-ATPase和ERK1/2之间的双向信号传导的分子细节。 AIM 2是确定Na，K-ATPase的α-1亚基是否在卡尔巴霍治疗的腮腺细胞中被激酶磷酸化。 AIM 3是检查ERK1/2的贡献以及细胞内Na对CIO细胞中Na，K-ATPase活性的变化，CIO细胞是一种永生的腮腺腺泡细胞系。我们将使用电生理技术来解决我们无法使用天然腮腺细胞解决的问题。 AIM 4是在减少细胞内ATP时检查腮腺腺泡细胞信号传导和功能的调节变化。 AIM 5是确定AMPK参与腮腺细胞信号传导和功能。 AMPK通过增加Na，K-ATPase活性的受体配体以Ouabain依赖性方式激活。我们建议这些调查领域将对腮腺细胞功能有更全面的了解，从而有助于未来的疗法来帮助唾液功能障碍。