Salivary gland hypofunction: genetic defects in signal

唾液腺功能减退：信号遗传缺陷

• 批准号: 6713312
• 负责人: Trevor J. Shuttleworth
• 金额: $ 14.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6713312
• 关键词: acinar cell; biological signal transduction; calcium flux; genetic disorder; human tissue; laboratory mouse; membrane transport proteins; muscarinic receptor; parotid gland; phospholipase C; protein kinase A; saliva; salivary glands; secretion; sodium potassium exchanging ATPase; xerostomias

Salivary gland hypofunction negatively impacts normal speech, mastication and general oral health. A significant proportion of these cases are of unknown origin (idiopathic). Our central hypothesis is that many of these cases reflect a disruption of the normal signaling pathways regulating the stimulation of salivary flow. The major mechanisms of stimulation of salivary gland fluid secretion involves muscarinic receptor- induced increases in intracellular Ca2+ concentration ([Ca2+]i), via activation of the phospholipase C/inositol triphosphate (PLC/InsP3) pathway, the details of which are fairly well-established. However, a substantial body evidence indicates the importance of a concurrent activation of cyclic AMP/protein kinase A (cAMP/PKA) signaling pathways along with the PLC/InsP3 pathway. This simultaneous activation of the two pathways profoundly potentiates overall fluid secretion via a mechanism that is, as yet, unclear. It is our hypothesis that proteins involved in this interaction are likely loci fort the underlying disruption seen in the diseased state. A major goal of this project is therefore to identify the key points of convergence of the two pathways in parotid acinar cells. Mouse parotid acinar cells will be utilized as a model system, however, the validity of the model will be confirmed in human tissue when available. We will examine the effects of PKA linked agonists on the generation and turnover of Insp3, and on the specific temporal and spatial features of the [Ca2+]i signals evoked by PLC- coupled agonists, both within and between acinar cells. The underlying mechanisms will be analyzed by identifying the molecular species and sub-cellular location of the individual signaling components involved, and by determining the properties of their regulation by PKA. In addition, potential interactions between PKA- and PLC-linked agonists at the level of the C1- and K+ conductances and the basolateral Na-2Cl-K co- transporter will be considered. The effects of potentiating combinations of agonists on the activation and modulation of individual Cl- and K+ conductances will be investigated, specifically focusing on those conductances demonstrated to be the most relevant in Subproject 2, and the nature of the effects determined. The activity of the co-transporter will also be assessed to determine if this is a potential site for potentiation by PKA-linked agonists. It is envisioned that these studies will identify loci which underlie the physiologically important regulation of salivary secretion, thereby increasing our understanding of the etiology of salivary gland dysfunction with a long term goal of designing effective therapies.

唾液腺功能低下会对正常言语产生负面影响， 咀嚼和一般口腔健康。其中很大一部分 病例来源不明（特发性）。我们的中心假设是 其中许多病例反映了正常信号通路的破坏 调节唾液流动的刺激。主要机制 刺激唾液腺液分泌涉及毒蕈碱受体- 诱导细胞内 Ca2+ 浓度 ([Ca2+]i) 增加，通过 磷脂酶 C/三磷酸肌醇的激活 (PLC/InsP3) 途径，其细节已相当完善。然而，一个 大量的身体证据表明了同时进行的重要性 激活环 AMP/蛋白激酶 A (cAMP/PKA) 信号传导 途径以及 PLC/InsP3 途径。这个同时 两条通路的激活极大地增强了整体液体 其分泌机制目前尚不清楚。我们的假设是 参与这种相互作用的蛋白质可能是潜在的基因座 患病状态下出现的破坏。该项目的一个主要目标是 因此，要确定这两条路径的交汇点 腮腺腺泡细胞。小鼠腮腺腺泡细胞将用作模型 然而，该模型的有效性将在人类身上得到证实 如果有纸巾的话。我们将检查 PKA 链接的影响 激动剂对 Insp3 的产生和更新以及特定的 PLC- 诱发的 [Ca2+]i 信号的时间和空间特征 腺泡细胞内和腺泡细胞之间的偶联激动剂。底层的 将通过识别分子种类和 所涉及的各个信号成分的亚细胞位置， 并通过 PKA 确定其调节特性。此外， PKA 和 PLC 连接激动剂之间潜在的相互作用 C1- 和 K+ 电导以及基底外侧 Na-2Cl-K co- 将考虑运输商。增强组合的效果 激动剂对单个 Cl- 和 K+ 的激活和调节 将调查电导，特别关注那些 电导被证明与子项目 2 最为相关，并且 影响的性质已确定。协同转运蛋白的活动将 还可以评估以确定这是否是潜在的增强位点 PKA 连接激动剂。预计这些研究将确定基因座 这是唾液的重要生理调节的基础 分泌，从而增加我们对唾液病因学的了解 腺体功能障碍的长期目标是设计有效的疗法。