Salivary gland hypofunction: genetic defects in signal

唾液腺功能减退：信号遗传缺陷

• 批准号: 6349645
• 负责人: Trevor J. Shuttleworth
• 金额: $ 22.18万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349645
• 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.

唾液腺功能减退会对正常的语言产生负面影响， 咀嚼和一般口腔健康。其中很大一部分 病例的原因不明（特发性）。我们的核心假设是， 这些病例中的许多反映了正常信号通路的中断， 调节唾液流的刺激。的主要机制 刺激唾液腺液体分泌涉及毒蕈碱受体， 诱导细胞内Ca 2+浓度（[Ca 2 +]i）增加，通过 磷脂酶C/三磷酸肌醇（PLC/InsP 3）的活化 路径，其中的细节是相当完善的。但 大量的身体证据表明并发症的重要性 环腺苷酸/蛋白激酶A（cAMP/PKA）信号传导的激活 沿着PLC/InsP 3途径。这种同时 这两条通路的激活深刻地增强了整体流体 通过一种机制分泌，目前还不清楚。我们假设 参与这种相互作用的蛋白质可能是潜在的 在疾病状态下看到的破坏。该项目的一个主要目标是 因此，为了确定这两种途径的汇合点， 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体中得到证实 可用的组织。我们将研究PKA相关的 受体激动剂对β 3的生成和周转的影响，以及对特异性 PLC诱发的[Ca 2 +]i信号的时空特征。 偶联激动剂，在腺泡细胞内和腺泡细胞之间。底层 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， 并通过测定PKA对其调节的性质。此外，本发明还提供了一种方法， PKA和PLC连接的激动剂之间的潜在相互作用， 的C1-和K+电导和基底外侧Na-2Cl-K共- 运输公司将予以考虑。的增效组合的效果 激活和调节单个Cl-和K+的激动剂 电导将被调查，特别是集中在那些 在子项目2中被证明最相关的电导，以及 影响的性质确定。协同转运体的活动将 还可以通过以下方式进行评估，以确定这是否是潜在的增强位点： PKA连接激动剂。据设想，这些研究将确定基因座 这是唾液分泌的重要生理调节的基础 分泌，从而增加我们对唾液腺炎病因的了解 腺体功能障碍的长期目标是设计有效的治疗方法。