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Molecular Mechanisms of Ion Transport by the SMG

SMG 离子传输的分子机制

基本信息

批准号：
8064727
负责人：
PHILIP J THOMAS
金额：
$ 36.16万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8064727
关键词：
Acinar Cell Bicarbonates Biological Models Cells Collaborations Cystic Fibrosis Transmembrane Conductance Regulator Data Dental caries Deterioration Development Disease Duct (organ) structure Ductal Electrolytes Enzymes Functional disorder Gene Silencing Goals Health Homeostasis Human Infection Iodine Ion Transport Ions Liquid substance Malignant neoplasm of thyroid Mammals Measures Mediating Membrane Potentials Metabolism Molecular Mucins Mus Nucleotides Oral cavity Oral health Parotid Gland Pathway interactions Permeability Pharmacology Pharmacotherapy Play Preventive Radiation therapy Reading Regulation Research Personnel Rest Role Saliva Salivary Glands Sjogren&apos s Syndrome Small Interfering RNA System Testing Time Toxic effect Work Xerostomia base basolateral membrane bean clinical application human DICER1 protein inhibitor/antagonist knock-down luminal membrane novel novel strategies prevent programs receptor saliva secretion seal symporter tool uptake

项目摘要

DESCRIPTION (provided by applicant): Fluid and electrolyte transport is the central function of salivary glands (SG) that is critical for oral health. A critical aspect of SG secretion is the secretion of nearly 140 mM HCO3- by the duct in which CFTR plays a central role. In addition to functioning as a Cl channel CFTR regulates the activity of several Cl and HCO3- transporters at the luminal membrane, including the newly discovered CI/HCO3 and I-SLC26 transporters (SLCTs). Another physiologically and clinically important function of the duct that has never been studied is I-transport and homeostasis. SGs are destroyed during 1311 therapy of thyroid cancers. Our contributions to this topic are a) the electrogenicity of the SLC26Ts, b) the role of the SLC26Ts in ductal HCO3- secretion and their regulation by CFTR, c) the regulation of CFTR by the SLC26Ts, d) expression of the I-transporter slc26a4 in SG cells. Recently we also found a novel ADP-activated H?7HCO3- permeable pathway in parotid acinar and duct cells. These findings led to a new hypothesis of ductal fluid and HCO3- secretion in which the bulk of HCO3- secretion is mediated by different SLC26Ts along the duct that are regulated by CFTR. In turn, the SLC26Ts suppress CFTR activity in the resting state and enhance CFTR activity at the stimulated state, which determines the final HCO3- content in the saliva. We also develop a new hypothesis of I-transport by SG cells. We will test this hypothesis in model systems AND NATIVE SG CELLS of WT, slc26a4-/- and slc26a6-/- mice in three Specific Aims: 1. Determine the transport mechanisms of the ADP- activated H?/HCO3- pathway and its role in ductal HCO3 secretion. 2. Study the role of slc26a4 and slc26a6 in SG fluid and HCO3- secretion using the KO mice. We also developed sealed ducts in primary culture in which transporters can be knocked down by dicer siRNA and in which we can measure directly fluid and HCO3- secretion. Systematic KD of SG SLC26Ts, pNBC and other HCO3- transporters will be used to study their role in ductal secretion. 3. Characterize the function of slc26a4 as an I-and HCO3- transporter and examine the role of the basolateral 2Na/l transporter NIS and the luminal slc26a4 in SG I-homeostasis and accumulation and their role in SG I-toxicity. The proposed work should advance our understanding of SG fluid and electrolyte secretion in health and disease and reveal for the first time the molecular bases for I-toxicity of SG during radiation therapy of thyroid cancers.

描述(申请人提供)：液体和电解质的运输是唾液腺(SG)的中心功能，对口腔健康至关重要。SG分泌的一个关键方面是近140 mM的HCO3-通过导管分泌，其中CFTR起核心作用。除了作为氯离子通道外，CFTR还调节腔膜上几种氯离子和HCO3-转运蛋白的活性，包括新发现的CI/HCO3和I-SLC26转运蛋白(SLCTs)。另一种从未被研究过的重要生理和临床功能是I-转运和动态平衡。SGS在1311年甲状腺癌治疗期间被破坏。我们对这一课题的贡献是：a)SLC26T的生电活性，b)SLC26T在导管HCO3分泌中的作用及其受CFTR的调节，c)SLC26T对CFTR的调节，d)I转运体SLC26A4在SG细胞中的表达。最近，我们还在腮腺腺泡和导管细胞中发现了一种新的ADP激活的H？7HCO3通透途径。这些发现导致了一种关于导管液体和HCO3分泌的新假说，其中大部分HCO3分泌是由CFTR调节的沿导管的不同SLC26T介导的。反过来，SLC26T在静息状态下抑制CFTR活性，而在刺激状态下增强CFTR活性，这决定了唾液中最终的HCO3-含量。我们还提出了SG细胞I-转运的新假说。我们将在WT、SLC26A4-/-和SLC26A6-/-小鼠的模型系统和天然SG细胞中验证这一假说，目的有三：1.确定ADP激活的H？/HCO3-途径的转运机制及其在导管HCO3分泌中的作用。2.利用KO小鼠研究sLC26a4和sLc26a6在脑脊液和HCO3分泌中的作用。我们还在原代培养中开发了密封的管道，在其中转运蛋白可以被DICER siRNA击倒，在其中我们可以直接测量液体和HCO3-的分泌。SgSLC26T、pNBC和其他HCO3-转运体的系统Kd将被用于研究它们在导管分泌中的作用。3.鉴定SLC26A4作为I-和HCO3-转运体的功能，研究底侧2Na/L转运体NIS和腔内SLC26A4在SG I-动态平衡和蓄积中的作用及其在SG I-毒性中的作用。这项工作将促进我们对SG液体和电解质分泌在健康和疾病中的理解，并首次揭示SG在甲状腺癌放射治疗中I-毒性的分子基础。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Corticosteroids correct aberrant CFTR localization in the duct and regenerate acinar cells in autoimmune pancreatitis.

皮质类固醇在自身免疫性胰腺炎中纠正管道中的异常CFTR定位和再生腺泡细胞。

DOI：
10.1053/j.gastro.2010.01.001
发表时间：
2010-05
期刊：
Gastroenterology
影响因子：
29.4
作者：
Ko SB;Mizuno N;Yatabe Y;Yoshikawa T;Ishiguro H;Yamamoto A;Azuma S;Naruse S;Yamao K;Muallem S;Goto H
通讯作者：
Goto H

IRBIT: it is everywhere.