Retinal degeneration and chloride channels.
视网膜变性和氯离子通道。
基本信息
- 批准号:6669318
- 负责人:
- 金额:$ 30.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-08-01 至 2007-07-31
- 项目状态:已结题
- 来源:
- 关键词:Xenopus antisense nucleic acid biophysics calcium calmodulin cell morphology cellular polarity chloride channels eye pharmacology human tissue ion transport ligands macular degeneration membrane permeability phagocytosis phosphorylation polymerase chain reaction protein quantitation /detection protein structure function retinal pigment epithelium rod cell site directed mutagenesis tamoxifen transfection voltage /patch clamp
项目摘要
DESCRIPTION (provided by applicant): The ability to read this page without magnification depends upon the integrity of the macula, a small region of the retina including the fovea. Macular degeneration is the leading cause of blindness in developed countries. Age-related macular degeneration (AMD) is a progressive degeneration of the macula that affects approximately 20% of individuals over the age of 65, but its causes remain unknown. The hypothesis driving this proposal is that CI currents play a role in phagocytosis of shed photoreceptor discs by the retinal pigment epithelium (RPE). Defects in this process can lead to macular degeneration as the result of accumulation of retinoids and lipofuscin pigment in the subretinal space. We propose that CI channels are important in normal phagocytosis because they are involved in the regulation of cell volume during ingestion of large quantities of outer segments. A variety of well-known CI channels including CFTR, CIC-2, CIC-3, and CIC-5 are expressed in RPE cells and recently it has been suggested that bestrophin, an RPE protein that causes Best macular dystrophy, is the founding member of a new family of CI channels. The goal of this project is to characterize the CI currents, especially bestrophin-mediated currents, that are expressed in RPE cells and to understand their function. There are three specific aims. (1) To determine the properties of bestrophin CI channels. We will test the hypothesis that bestrophins are subunits of a chloride channel by patch clamp analysis of heterologously expressed bestrophins. (2) To characterize chloride channels in RPE cells. This aim tests the hypothesis that several types of CI channels are functionally specialized for specific RPE functions. The strategy is to use whole-cell and patch clamp recording to characterize CI channels in RPE cells and to compare them to the properties of known CI channels, including bestrophin. (3) To determine the role of CI channels in photoreceptor disc phagocytosis. This aim will test the hypothesis that CI channels are important in phagocytosis of rod outer segments by RPE cells. This hypothesis will be tested by determining the effects of pharmacological inhibitors and antisense knockdown of CI currents on the phagocytosis of rod outer segments by RPE.
描述(申请人提供):能否在不放大的情况下阅读本页取决于黄斑的完整性,黄斑是包括中心凹在内的视网膜的一个小区域。黄斑变性是发达国家致盲的主要原因。年龄相关性黄斑变性(AMD)是一种进行性黄斑变性,影响大约20%的65岁以上的人,但其原因尚不清楚。支持这一假设的假设是CI电流在视网膜色素上皮(RPE)吞噬脱落的光感受器盘中发挥作用。这一过程中的缺陷可导致黄斑变性,原因是视网膜下腔内积累了类维A酸和脂褐素色素。我们认为CI通道在正常的吞噬作用中是重要的,因为它们参与了摄取大量外层片段时细胞体积的调节。许多著名的CI通道包括CFTR、CIC-2、CIC-3和CIC-5在RPE细胞中表达,最近有研究表明,Bestrophin是一种导致最佳黄斑营养不良的RPE蛋白,是一个新的CI通道家族的创始成员。本项目的目的是描述RPE细胞表达的CI电流,特别是Bestrophin介导的电流,并了解其功能。有三个具体目标。(1)确定Bestrophin CI通道的特性。我们将通过对异源表达的bestrophins进行膜片钳分析来检验bestrophins是氯离子通道亚单位的假设。(2)研究视网膜色素上皮细胞的氯离子通道。这一目的验证了几种类型的CI通道在功能上专用于特定RPE功能的假设。该策略是使用全细胞和膜片钳记录来表征RPE细胞中的CI通道,并将它们与已知CI通道的特性进行比较,包括Bestrophin。(3)探讨CI通道在视盘吞噬功能中的作用。这一目的将检验CI通道在RPE细胞吞噬视杆细胞外段中的重要作用的假说。这一假说将通过确定药物抑制剂和反义敲除CI电流对RPE吞噬视杆外段的影响来验证。
项目成果
期刊论文数量(0)
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H. CRISS HARTZELL其他文献
H. CRISS HARTZELL的其他文献
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{{ truncateString('H. CRISS HARTZELL', 18)}}的其他基金
Molecular Physiology of TMEM16/Anoctamin Proteins
TMEM16/Anoctamin 蛋白的分子生理学
- 批准号:
10466884 - 财政年份:2019
- 资助金额:
$ 30.4万 - 项目类别:
Molecular Physiology of TMEM16/Anoctamin Proteins
TMEM16/Anoctamin 蛋白的分子生理学
- 批准号:
10245101 - 财政年份:2019
- 资助金额:
$ 30.4万 - 项目类别:
Molecular Physiology of TMEM16/Anoctamin Proteins
TMEM16/Anoctamin 蛋白的分子生理学
- 批准号:
10017300 - 财政年份:2019
- 资助金额:
$ 30.4万 - 项目类别:
Ion Channel and Lipid Scramblase Functions of Anoctamins: Roles in Myopathy
Anoctamins 的离子通道和脂质扰乱酶功能:在肌病中的作用
- 批准号:
9327656 - 财政年份:2015
- 资助金额:
$ 30.4万 - 项目类别:
Ion Channel and Lipid Scramblase Functions of Anoctamins: Roles in Myopathy
Anoctamins 的离子通道和脂质扰乱酶功能:在肌病中的作用
- 批准号:
9027618 - 财政年份:2015
- 资助金额:
$ 30.4万 - 项目类别:
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