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; 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.

唾液腺功能低下对正常语音产生负面影响， 咀嚼和一般口腔健康。其中很大一部分 病例是未知的起源（特发性）。我们的中心假设是 其中许多情况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+浓度的增加（[Ca2+] i），通过 磷脂酶C/肌醇三磷酸的激活（PLC/INSP3） 途径，其细节是相当良好的。但是， 大量的身体证据表明并发的重要性 循环AMP/蛋白激酶A（CAMP/PKA）信号的激活 路径与PLC/INSP3途径一起。这个同时 这两种途径的激活深刻增强了总体流体 通过一种机制的分泌，迄今为止尚不清楚。我们的假设是 参与这种相互作用的蛋白质可能是基础的基因堡 在患病状态下看到的破坏。这个项目的主要目标是 因此，以确定两种途径的收敛的关键点 腮腺腺泡细胞。小鼠腮腺腺泡细胞将被用作模型 但是，系统将在人类中确认模型的有效性 组织，如果有的话。我们将研究PKA链接的效果 激动者对INSP3的产生和营业额以及特定的激动剂 [Ca2+] i信号的时间和空间特征由PLC-引起 在腺泡细胞之间和之间的耦合激动剂。基础 通过识别分子物种和 涉及各个信号成分的亚细胞位置， 并通过确定PKA调节的特性。此外， PKA-和PLC连接激动剂之间的潜在相互作用在该水平上 C1-和K+电导以及基底外侧Na-2cl-K共同 将考虑转运蛋白。增强组合的影响 激动剂对单个Cl-和K+的激活和调节 将调查电导，特别关注这些电导 电导率证明是第2次的最相关的电导 确定效果的性质。共转运者的活动将 还可以评估以确定这是否是通过 与PKA相关的激动剂。可以预见，这些研究将确定基因座 唾液对生理上重要的调节的基础 分泌，从而增加我们对唾液病因的理解 腺功能障碍具有设计有效疗法的长期目标。