Salivary gland hypofunction & genetic defects

唾液腺功能减退

基本信息

批准号：
6867409
负责人：
JAMES E MELVIN
金额：
$ 17.81万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Approximately 20% of xerostomia cases are of unknown etiology. Many of these idiopathic "dry mouth" disorders are likely due to genetic defects in the fluid transport mechanism. An initial step in the development of treatments for these latter individuals is to identify the key transport proteins involved in the fluid secretion process. Secretion is driven by the activation of K+ and C1-channels. Several distinct types of K+ and Cl- channels have been functionally identified in salivary acinar cells, but only a few of these have been identified as specific gene products. Some of the properties of these proteins have been determined but little is known about the specific contribution these channels make to the fluid secretion process. Thus, the long-term objective of this Subproject is to identify the K+ and Cl-channel proteins essential for saliva production in human and mouse parotid glands. We will attempt to corroborate our findings in humans identified as suffering from idiopathic dry mouth as part of Subproject 3. Aim 1 will distinguish which of the different K+ and Cl-channels are functionally important to the production of saliva by characterizing channel different K+ and Cl-channels are functionally important in the production of saliva by characterizing channel biophysics. We will coordinate our efforts with Subproject 1 in order to determine the physiologically relevant effects of agonist-induced signals on the activation of K+ and Cl-channels. In Aim 2, the molecular identity of the channels expressed in human and mouse parotid acinar cells will be determined by cloning cDNAs that encode the corresponding K+ and Cl- channel proteins. The results from Aims 1 and 2, as well as those from Subproject 1, will provide essential information for predicting the role of individual channels in the secretion process. However, owing to the lack of different pharmacology for many channels in the test of the importance of a given protein can be obtained most easily by studying an animal defective in the expression of the channel. In Aim 3 the functional significance of specific channel proteins will be determined by examining the effects of gene disruption. Mice lacking expression of two different Cl-channels are currently available for study (CFTR and C1C3). Additional channels found to play critical roles in secretion that can not be selectively blocked with inhibitors will be eliminated in mice by targeted recombination. The results of these studies are expected to uncover the genetic basis for some forms of idiopathic salivary gland hypofunction and to provide a foundation for the development of treatments for these individuals as well as those patients suffering from other forms of salivary gland dysfunction.

大约有20％的静态病例是病因未知。这些特发性“口干”疾病中的许多可能是由于流体转运机制中的遗传缺陷所致。这些后一个个体的治疗发展的第一步是确定流体分泌过程中涉及的关键转运蛋白。分泌是由K+和C1通道的激活驱动的。在唾液腺泡细胞中已在功能上鉴定了几种不同类型的K+和Cl-通道，但其中只有少数被鉴定为特定基因产物。这些蛋白质的某些特性已经确定，但对这些渠道对流体分泌过程的特定贡献知之甚少。因此，该副本的长期目标是确定人和小鼠腮腺唾液至关重要的K+和CL通道蛋白。我们将试图证实我们在人类中的发现，被认为是特发性干口的苦难3。AIM1将区分哪些不同的K+和CL通道中的哪些通过表征不同的K+和Cl-Cl-nannels在功能上很重要，而Cl-nannels在功能上很重要，而Cl-nannels在表征Saliva的生产中通过表征Channel Biophyphysic的生产而功能上很重要。我们将与subproject 1协调我们的努力，以确定激动剂诱导的信号对K+和CL通道激活的生理相关影响。在AIM 2中，将通过克隆cDNA来确定在人和小鼠腮腺细胞中表达的通道的分子身份，该cDNA编码相应的K+和Cl-通道蛋白。 AIM 1和2的结果以及subproject 1的结果将为预测单个渠道在分泌过程中的作用提供必不可少的信息。但是，由于在测试给定蛋白质重要性的许多通道中缺乏不同的药理学，可以通过研究在通道表达中有缺陷的动物来获得最容易获得。在AIM 3中，特定通道蛋白的功能意义将通过检查基因破坏的影响来确定。目前可以研究缺乏两种不同CL通道表达的小鼠（CFTR和C1C3）。发现在分泌中起关键作用的其他通道将通过靶向重组在小鼠中被抑制剂选择性地阻塞。这些研究的结果预计将揭示某些形式的特发性唾液腺功能障碍的遗传基础，并为这些人以及患有其他形式的唾液腺功能障碍的患者提供治疗的基础。