Novel Calcium Signaling Pathways in the Salivary Gland

唾液腺中的新型钙信号通路

基本信息

批准号：
8637247
负责人：
DAVID R GIOVANNUCCI
金额：
$ 21.54万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637247
关键词：
Acetylcholine Acinar Cell Acinus organ component Adrenergic Receptor Agonist Animals Astrocytes Automobile Driving Benchmarking Biochemical Calcium Signaling Cells Complex Consensus Coupling Data Dependence Disease Enzymes Esthesia Event Fluids and Secretions Generations Goals Health Heart Atrium Human Intervention Investigation Ion Channel Knowledge Learning Life Liquid substance Lymphocyte Mammalian Cell Measures Mediating Mediator of activation protein Molecular Mouth Diseases Mus Muscarinic Acetylcholine Receptor Muscle Cells NAADP Neurotransmitters Norepinephrine Operative Surgical Procedures Optics Oral Oral health Organ Organelles Pancreas Parotid Gland Pathway interactions Patients Pattern Physiological Play Production Protein Secretion Proteins Quality of life Receptor Activation Residual state Role Saliva Salivary Salivary Gland Tissue Salivary Glands Sea Urchins Signal Pathway Signal Transduction Sjogren&apos s Syndrome Slice Sodium Chloride Stimulus Testing Tissues Water Movements Work Xerostomia cell type cholinergic design egg functional restoration gene therapy improved inorganic phosphate insight mouse model nicotinic acid adenine dinucleotide novel receptor regenerative relating to nervous system research study saliva secretion small molecule success treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Salivary gland function is essential for oral and general health, and oral diseases that diminish saliva production significantly impact one's quality of life. Sympathetic and parasympathetic input to salivary glands rapidly and dynamically control the rate of salivary flow by the coordinated activities of ion channels and transporters that induce water movement and promote the exocytotic secretion of digestive enzyme and other proteins. This control is achieved by mechanisms that generate complex patterns of cytosolic Ca2+ observed in acinar cells. Whereas the consequences of these signals for fluid and protein secretion are subjects of on- going investigations, the potential role that acidic vacuolar Ca2+ stores play in the triggering or globalization of receptor mediated Ca2+ signals has not yet been appreciated. The identification of acidic, vacuolar organelles as a releasable Ca2+ store in some cells was revealed by the discovery that nicotinic acid adenine dinucleotide phosphate (NAADP) functions as a newly recognized highly potent Ca2+ mobilizing messenger that initiates or sensitizes agonist-stimulated Ca2+ signals in a variety of mammalian cells. However, it is surprising that our knowledge of this newly elaborated fundamental Ca2+ signaling pathway lags when compared to some other exocrine organs. The central hypothesis is that NAADP-evoked Ca2+ release from acidic compartments exerts critical regulatory control over salt and protein secretion in parotid acinar cells. The goal of the proposal is to elucidate the role of this novel pathway in salivation by directly measuring saliva flow in normal (background strain) and mouse models of Sjogren's syndrome (SS). This will be achieved in combination with pharmacological interventions or by measuring Ca2+ and secretory dynamics in parotid and submandibular acinar cell clusters, organ slices or live animals. In addition, the role of NAADP in Ca2+ and secretory dynamics will also be assessed in parotid and submandibular tissues obtained following surgery from healthy or SS patients. The working hypothesis is that diminished NAADP signaling plays an important role in SS. We will i) demonstrate agonist-induced formation of NAADP, ii) identify the relevant molecular machinery for NAADP-mediated signaling and iii) elucidate the functional consequences of NAADP to Ca2+ signals in parotid acini. Importantly, this work will advance our understanding of fundamental signaling pathways relevant for salivary gland function and identify potential targets for augmenting or restoring function for patients suffering reduced saliva formation.

描述（由申请人提供）：唾液腺功能对于口腔和一般健康至关重要，口腔疾病会显着影响唾液的生产。对唾液腺的交感神经和副交感神经输入通过离子通道和转运蛋白的协调活性迅速，动态地控制唾液流动的速率，这些活动诱导水运动并促进消化酶和其他蛋白质的胞吐分泌。通过在腺泡细胞中观察到的胞质Ca2+复杂模式的机制来实现此控制。尽管这些信号对液体和蛋白质分泌的后果是对正在进行的研究的受试者，但尚未理解酸性液泡液泡Ca2+存储在受体介导的Ca2+信号的触发或全球化中的潜在作用。发现烟酸腺苷磷酸腺苷（NAADP）鉴定出某些细胞中可释放的Ca2+储存的酸性，可鉴定为可识别的高度有效的CA2+动员Messenger，从而启动或敏感了抗强化的Ca2+信号+ MAMAMALIAN MAMMALIAN。然而，令人惊讶的是，与其他一些外分泌器官相比，我们对这种新详细阐述的基本CA2+信号通路的了解滞后。中心假设是，NAADP引起的Ca2+从酸性室中释放，对腮腺腺泡细胞中的盐和蛋白质分泌施加了严格的调节控制。该提案的目的是通过直接测量正常（背景应变）和Sjogren综合征（SS）的小鼠模型来阐明这种新途径在唾液中的作用。这将与药理学干预措施结合使用，或通过测量腮腺和下颌下细胞簇，器官切片或活动物中的Ca2+和分泌动力学来实现。此外，NAADP在CA2+和分泌动力学中的作用也将在健康或SS患者手术后获得的腮腺和下颌组织中评估。工作假设是，NAADP信号降低在SS中起重要作用。我们将证明激动剂诱导的NAADP的形成，ii）确定NAADP介导的信号传导的相关分子机械，iii）阐明了NAADP对腮腺炎中Ca2+信号的功能后果。重要的是，这项工作将提高我们对与唾液腺功能相关的基本信号通路的理解，并确定增加唾液形成降低的患者的潜在靶标。