Endosome regulated photoreceptor protein trafficking
Endosome regulated photoreceptor protein trafficking
批准号:
9915929
负责人:
CHING-HWA SUNG
金额:
$42.38万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-01 至 2022-04-30
关键词:
3-DimensionalAddressAdultAffectAgeAnimal ModelBindingBiogenesisBiological AssayBlindnessCell DeathCellsCellular StressComplexConfocal MicroscopyCritical PathwaysDefectDestinationsDevelopmentDiseaseDisease modelEarly EndosomeElectron MicroscopyEndoplasmic ReticulumEndosomesEtiologyExcisionGene DeletionGenesGeneticGenetic HeterogeneityGoalsGolgi ApparatusHomeostasisHumanIndividualInvestigationKnowledgeLeadLightLiteratureMADHIP geneMass Spectrum AnalysisMembraneMethodsModelingMolecularMorphogenesisMusMutationNeuronsNight BlindnessOrganellesPathologicPathologyPathway interactionsPatientsPeripheralPhenotypePhotoreceptorsPhysiologicalPlayPresynaptic TerminalsProcessProteinsProteomicsResearchResolutionResourcesRetinaRetinal DegenerationRetinal DystrophyRetinitis PigmentosaRhodopsinRodRoleRouteScanning Electron MicroscopySignal TransductionSiteSmad ProteinsSorting - Cell MovementStructureSystemTechniquesTestingTimeTracerTransgenesVisionbasecell typeeffective therapyextracellularflyimprovedin vivoinducible gene expressioninnovationinsightlegally blindmouse modelmutantneuropathologynovelnovel therapeuticsprotein complexprotein transportproteostasisresponseretinal rodssuccesssynaptic functiontherapy designtraffickinguptakevector
中文摘要
项目摘要
视网膜色素变性(RP)导致所有年龄段的个体不可逆的失明。它影响约3,500人中的1人
国际吧虽然RP最初的特点是夜盲症和周边视力丧失,大多数RP患者
在40岁时失去中心视力并成为法定盲人。没有治疗方法可以减缓或停止
视力丧失视杆细胞中的光吸收蛋白视紫红质的错误定位是一个共同的标志
许多动物模型的RP。本申请的长期目标是剖析分子途径
这是视紫红质的分类和传递的基础,并决定了它与疾病的相关性。这些信息
将加速发现RP和其他视网膜退行性疾病的新疗法。在
哺乳动物的视杆细胞是高度区室化的,视紫红质是在生物合成
局限于内节的细胞器。然后将视紫红质矢量递送并浓缩在
外段(OS)。视紫红质通过内质网-高尔基体途径运输,
虽然已经研究过,但是内体在视紫红质的OS靶向中的重要性尚不清楚。在许多其他细胞中
类型,内体作为蛋白质的关键分选站,处于多种细胞内
贩运途径。果蝇视紫红质的内体积累时间延长,
依赖性视网膜变性我们的初步结果表明,新合成的视紫红质
在体内通过小鼠视杆细胞的内体区室。的OS目标信号
视紫红质与早期内体蛋白特异性蛋白SARA结合。小鼠视杆细胞中的SARA缺乏不仅
导致视紫红质错误定位,但也导致内溶酶体系统中的其他几种细胞缺陷。在这
应用,我们将测试中心假设,在哺乳动物杆的trans-binding内体途径的关键
调节视紫红质的OS靶向的保真度和效率。首先,我们将讨论
RP突变型视紫红质在转运至OS期间异常保留在内体中,以及是否
这种缺陷扰乱了其它内膜的稳态(Aim 1)。我们将产生多个,
互补的小鼠模型,以检查反式内体途径在形态发生中的作用,
OS及其视紫红质表达(Aim 2)。我们还将分析通过蛋白质转运的杆状蛋白,
内体系统,并表征其与关键内体运输调节剂(Aim 3)的相互作用。我们
将通过应用最先进的技术,如杆状病毒特异性诱导基因,
表达和基因缺失,超分辨共聚焦显微镜,相关光电子显微镜,
和3D扫描电子显微镜。通过提供光感受器蛋白运输的机制见解,
和OS的生物发生,这项研究将有助于RP和相关疾病的新疗法的发展。
疾病
英文摘要
PROJECT SUMMARY
Retinitis pigmentosa (RP) causes irreversible blindness in individuals of all ages. It affects ~1 in 3,500 people
worldwide. While RP is initially characterized by night blindness and peripheral vision loss, most RP patients
lose their central vision and become legally blind by the age of 40. There is no treatment to slow or stop
vision loss. Mislocalization of the light-absorbing protein rhodopsin in the rods is a common hallmark shared
by many animal models of RP. The long-term objective of this application is to dissect the molecular pathway
that underlies the sorting and delivery of the rhodopsin and determine its disease relevance. This information
will accelerate the discovery of new treatments for RP and other retinal degenerative diseases. In the
mammalian rods, which are highly compartmentalized, rhodopsin is synthesized in the biosynthetic
organelles confined to the inner segment. Rhodopsin is then vectorially delivered to and concentrated in the
outer segment (OS). While rhodopsin’s trafficking through the endoplasmic reticulum-Golgi pathway has
been investigated, the importance of the endosome in rhodopsin’s OS targeting is unclear. In many other cell
types, the endosome s erves as a key sorting station for proteins at the crossroads of multiple intracellular
trafficking pathways. Prolonged endosomal accumulation of fly rhodopsin has been shown to lead to light-
dependent retinal degeneration. Our preliminary results showed that the newly-synthesized rhodopsin
transits through the endosomal compartments in mouse rods in vivo. The OS targeting signal of the
rhodopsin binds to an early endosome-specific protein, SARA. SARA deficiency in mouse rods not only
causes rhodopsin mislocalization but also several other cellular defects in the endolysosomal system. In this
application, we will test the central hypothesis that in mammalian rods the trans-endosomal pathway critically
regulates the fidelity and the efficiency of the OS targeting of rhodopsin. First, we will address whether the
RP mutant rhodopsins are retained in the endosomes abnormally during their transit to the OS, and whether
this defect perturbs the homeostasis of other endomembranes (Aim1). We will generate multiple,
complementary mouse models to examine the role of the trans-endosomal pathway in the morphogenesis of
the OS and its rhodopsin expression (Aim2). We will also profile the rod proteins that transit through the
endosomal system and characterize their interaction with key endosomal trafficking regulators (Aim3). We
will achieve these aims by applying state-of-the-art techniques such as rod-specific inducible gene
expression and gene deletion, super-resolution confocal microscopy, correlative light-electron microscopy,
and 3D scanning electron microscopy. By providing mechanistic insights on photoreceptor protein trafficking
and OS biogenesis, this research will contribute to the development of new therapies for RP and related
diseases.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Modeling and mechanistic investigation of a novel dry AMD mouse model with CLIC4 deleted in RPE
-
批准号:10475752
-
项目类别:
-
资助金额:$41.1万
-
财政年份:2021
-
负责人:CHING-HWA SUNG
-
依托单位:
Modeling and mechanistic investigation of a novel dry AMD mouse model with CLIC4 deleted in RPE
-
批准号:10279736
-
项目类别:
-
资助金额:$42.38万
-
财政年份:2021
-
负责人:CHING-HWA SUNG
-
依托单位:
Modeling and mechanistic investigation of a novel dry AMD mouse model with CLIC4 deleted in RPE
-
批准号:10626102
-
项目类别:
-
资助金额:$42.38万
-
财政年份:2021
-
负责人:CHING-HWA SUNG
-
依托单位:
Endosome regulated retinal homeostasis and disease
-
批准号:10668691
-
项目类别:
-
资助金额:$53.53万
-
财政年份:2018
-
负责人:CHING-HWA SUNG
-
依托单位:
Structural and functional integrity and microenvironment of RPE cells
-
批准号:8607949
-
项目类别:
-
资助金额:$48.07万
-
财政年份:2006
-
负责人:CHING-HWA SUNG
-
依托单位:
Cytoskeleton's role in RPE's structure and function
-
批准号:7922004
-
项目类别:
-
资助金额:$32.3万
-
财政年份:2006
-
负责人:CHING-HWA SUNG
-
依托单位:
Cytoskeleton's role in RPE's structure and function
-
批准号:7475045
-
项目类别:
-
资助金额:$31.97万
-
财政年份:2006
-
负责人:CHING-HWA SUNG
-
依托单位:
Cytoskeleton's role in RPE's structure and function
-
批准号:7663051
-
项目类别:
-
资助金额:$32.63万
-
财政年份:2006
-
负责人:CHING-HWA SUNG
-
依托单位:
Cytoskeleton's role in RPE's structure and function
-
批准号:7150518
-
项目类别:
-
资助金额:$33.6万
-
财政年份:2006
-
负责人:CHING-HWA SUNG
-
依托单位:
Cytoskeleton's role in RPE's structure and function
-
批准号:7266915
-
项目类别:
-
资助金额:$32.63万
-
财政年份:2006
-
负责人:CHING-HWA SUNG
-
依托单位:
Structural and functional integrity and microenvironment of RPE cells
-
批准号:8415828
-
项目类别:
-
资助金额:$46.59万
-
财政年份:2006
-
负责人:CHING-HWA SUNG
-
依托单位:
Structural and functional integrity and microenvironment of RPE cells
-
批准号:8238668
-
项目类别:
-
资助金额:$49.05万
-
财政年份:2006
-
负责人:CHING-HWA SUNG
-
依托单位:
MODULE--TISSUE AND CELL CULTURE
-
批准号:6949304
-
项目类别:
-
资助金额:$11.74万
-
财政年份:2005
-
负责人:CHING-HWA SUNG
-
依托单位:
MOLECULAR BASIS OF PROTEIN TRANSPORT IN PHOTORECEPTORS
-
批准号:6138199
-
项目类别:
-
资助金额:$24.29万
-
财政年份:1996
-
负责人:CHING-HWA SUNG
-
依托单位:
MOLECULAR BASIS OF PROTEIN TRANSPORT IN PHOTORECEPTORS
-
批准号:2856948
-
项目类别:
-
资助金额:$23.36万
-
财政年份:1996
-
负责人:CHING-HWA SUNG
-
依托单位:
MOLECULAR BASIS OF PROTEIN TRANSPORT IN PHOTORECEPTORS
-
批准号:6489832
-
项目类别:
-
资助金额:$33.9万
-
财政年份:1996
-
负责人:CHING-HWA SUNG
-
依托单位:
Molecular Basis of Protein Transport in Photoreceptor
-
批准号:8599460
-
项目类别:
-
资助金额:$63.55万
-
财政年份:1996
-
负责人:CHING-HWA SUNG
-
依托单位:
MOLECULAR BASIS OF PROTEIN TRANSPORT IN PHOTORECEPTORS
-
批准号:2020030
-
项目类别:
-
资助金额:$21.74万
-
财政年份:1996
-
负责人:CHING-HWA SUNG
-
依托单位:
MOLECULAR BASIS OF PROTEIN TRANSPORT IN PHOTORECEPTORS
-
批准号:2634459
-
项目类别:
-
资助金额:$21.79万
-
财政年份:1996
-
负责人:CHING-HWA SUNG
-
依托单位:
Molecular Basis of Protein Transport in Photoreceptor
-
批准号:7029999
-
项目类别:
-
资助金额:$42.0万
-
财政年份:1996
-
负责人:CHING-HWA SUNG
-
依托单位:
海外基金