Membrane Protein Transport in Photoreceptors

光感受器中的膜蛋白转运

基本信息

批准号：
8756527
负责人：
WOLFGANG BAEHR
金额：
$ 37.25万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8756527
关键词：
Abbreviations Address Adenylate Cyclase Affect Afferent Neurons Affinity Chromatography Alleles Animals Antibodies Binding Binding Proteins Brain Calcium-Binding Proteins Calmodulin Cell Culture Techniques Cell Line Cell Nucleus Cell membrane Cells Cellular biology Choroideremia Cilia Cilium Microtubule Complex Defect Disease Docking Dominant-Negative Mutation Drosophila genus Dysosmia EF Hand Motifs Endoplasmic Reticulum Etiology Exhibits Family Genes Golf Golgi Apparatus Green Algae Guanosine Triphosphate Phosphohydrolases Guanylate Cyclase Human Hydrocephalus In Vitro Integral Membrane Protein Joubert syndrome Knock-out Knockout Mice Life Male Infertility Mammalian Cell Membrane Membrane Protein Traffic Membrane Proteins Membrane Transport Proteins MicroRNAs Microtubule-Organizing Center Microtubules Modeling Mus Opsin Pathway interactions Patients Phenotype Photons Photoreceptors Phototransduction Plants Process Protein Isoforms Proteins Regulation Research Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Ribosomes Role Site Situs Inversus Spermiogenesis Structure Syndrome Tail Tamoxifen Technology Testing Transducin Trimethoprim-Sulfamethoxazole Vesicle Virus Xenopus analog base ciliopathy cilium biogenesis gene replacement therapy gene therapy human disease immortalized cell kinetosome member mouse model mutant peripherin photoreceptor degeneration polypeptide protein transport public health relevance research study retinal rods small hairpin RNA sperm cell trafficking trans-Golgi Network vector

项目摘要

DESCRIPTION (provided by applicant): Photoreceptor outer segment membranes, the site of initial photon capture initiating phototransduction, undergo renewal with total replacement occurring at ten day intervals throughout life. A challenge to cellular integrity concerns the post biosynthetic delivery of replacement proteins from the inner, to the outer, segment over the lifetime of the photoreceptor. Complex trafficking pathways require multiple components, such as acyl-binding proteins, Rab GTPases and centrins. This application will identify: i) key Rab GTPases involved in vesicular transport of membrane protein, and ii) centrins participating in ciliary transport. Aim 1 will focus on Rab GTPases in photoreceptor vesicular transport. Rab (Ras analog in brain) proteins are members of the Ras supergene family involved mainly in membrane protein trafficking. More than 70 distinct Rab polypeptides have been identified. Aim 1a focuses on Rab8 and Rab11 isoforms which are known to be important for photoreceptor trafficking in Xenopus and Drosophila models. Surprisingly, a mouse Rab8a/Rab11a double knockout does not produce a defective trafficking phenotype. Therefore, we will focus on closely-related isoforms to identify key Rab proteins responsible for membrane protein organization and rhodopsin trafficking. Aim 1b investigates Rab28, shown recently associated with recessive human cone/rod dystrophy. Aim 2 will examine the function of centrosomal proteins, called "centrins," which are 20kD EF- hand calcium binding proteins (four EF-hand motifs) of the calmodulin superfamily. Centrins were first described in unicellular green algae where they are associated with the flagellar basal apparatus. Photoreceptor centrins (isoforms 1-4) are located in the ciliary lumen and basal body where they associate with transducin via its T¿?-subunits. One hypothesis is that centrins may be involved in regulation of transducin translocation from the outer, to the inner, segment or vice-versa. As preliminary results, we found that centrin1 is required for the nucleus-basal body connection during mouse spermiogenesis, and centrin2 regulates trafficking of ACIII and channel subunits in olfactory sensory neurons. This aim seeks to identify the roles of photoreceptor centrin3 and centrin4 which associate strongly with the basal body and/or connecting cilium axoneme. We expect to generate mouse models of syndromic disease with retina degeneration, e.g., Joubert or Senior-Loken syndromes.

描述（由申请人提供）：光感受器的外部段膜，初始光转移的位点，全生而为止在10天的间隔内发生总替换。在光感受器的寿命上，内部的生物合成递送，需要多个成分，例如酰基结合蛋白，RAB GTPase和Centrins。膜蛋白和II。因此，在果蝇模型中，我们将重点介绍与膜蛋白1B的同工蛋白相关的同工蛋白。是20kD的钙结合蛋白（四个EF手基序），是钙调蛋白超家族的，它们与鞭毛基底型相关。通过它的 - 一个假设是一种假设，是中心蛋白可以从外部易位，作为初步结果，我们发现中心是在小鼠精子发生过程中需要核 - 基质体连接的核。感官神经元。