Salivary gland hypofunction: genetic defects in signal

唾液腺功能减退对正常语言有负面影响， 咀嚼和一般口腔健康。其中很大一部分是 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中断。 调节唾液流动的刺激。其主要作用机制是 刺激唾液腺分泌液涉及M受体- 细胞内钙离子浓度([Ca~(2+)]i)通过 磷脂酶C/三磷酸肌醇(PLC/InsP3)的激活 路径，其细节是相当确定的。然而，a 大量的身体证据表明了同时发生 环磷酸腺苷/蛋白激酶A信号通路的激活 途径包括PLC/InsP3途径。这是同步的 这两个通路的激活深刻地增强了整体体液 通过一种机制进行分泌，目前尚不清楚。我们的假设是 参与这种相互作用的蛋白质很可能是潜在的 在患病的状态下可以看到的破坏。这个项目的一个主要目标是 因此，要找出这两条路径的交汇点 腮腺腺泡细胞。将以小鼠腮腺腺泡细胞为模型 系统，但模型的有效性将在人类身上得到证实 组织，如果有的话。我们将研究与PKA挂钩的影响 激动剂对Insp3的产生和周转，以及对特异性 PLC诱发[Ca~(2+)]_i信号的时空特征 腺泡细胞内和腺泡细胞间的偶联激动剂。潜在的 将通过鉴定分子物种和分子种类来分析机理 所涉及的各个信令组件的亚蜂窝位置， 并通过确定它们被PKA调控的性质。此外, PKA和PLC连接的激动剂在水平上的潜在相互作用 C_1~-、K~+电导和基侧Na-2Cl-K共电导 运输商将被考虑。增强药物组合的效果 激动剂对单个氯离子和钾离子的激活和调节 电导性将被调查，特别是那些 在分项目2中，电导被证明是最相关的，以及 影响的性质决定了。联合运输商的活动将 也要进行评估，以确定这是否为潜在的增强部位 PKA相关激动剂。据设想，这些研究将确定基因座 这是唾液重要的生理调节的基础 分泌物，从而增加我们对唾液病因的了解 腺体功能障碍，长期目标是设计有效的治疗方法。

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.