Hermansky Pudlak Syndrome & melanosome formation
赫曼斯基普德拉克综合症
基本信息
- 批准号:8117490
- 负责人:
- 金额:$ 50.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-05-01 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Protein Complex 1Adaptor Protein Complex 2Adaptor Protein Complex 3Adaptor Signaling ProteinAffectAnabolismBindingBiogenesisBiological ModelsCapsid ProteinsCellsColorComplexDataDefectDevelopmentDiagnosticDiseaseDockingEarly EndosomeEndosomesEquilibriumEtiologyEventEyeFailureFamily memberFibrosisGenesGeneticGoalsGrantGuanosine Triphosphate PhosphohydrolasesHealthHemorrhageHereditary DiseaseHermanski-Pudlak SyndromeHumanImmuneIntegral Membrane ProteinLinkLungLysosomesMalignant NeoplasmsMediatingMelaninsMelanosomesMembraneMembrane FusionMolecularMusMutationOculocutaneous AlbinismOrganellesPathologyPathway interactionsPatientsPhasePigment Epithelium of EyePigmentsPredispositionProteinsPublishingPuerto RicoRecyclingRelative (related person)SNAP receptorSkinSmall Interfering RNASorting - Cell MovementStagingStructureSymptomsTestingTissuesTreatment ProtocolsVesicleVisionWorkanterograde transportcell motilitycell typeendosome membraneinsightlysosomal proteinsmalformationmelanocytemembermouse modeloverexpressionprotein complexprotein functionprotein transportrab11 proteinretrograde transportsensorsyntaxin 13tooltrafficking
项目摘要
DESCRIPTION (provided by applicant): Melanosomes are tissue-specific intracellular organelles that function in the biosynthesis, storage, and transport of melanins in pigment cells of the eye and skin melanocytes. Melanosomes form within these cells through progressive developmental stages by the ordered delivery of specific protein contents from early endocytic organelles. Defects in melanosome formation cause oculocutaneous albinism (OCA), a condition associated with impaired vision and enhanced cancer susceptibility in the skin and eye. OCA is one of several systemic conditions associated with the Hermansky-Pudlak syndromes (HPS), genetic disorders in which melanosomes and other related tissue-specific organelles fail to form properly. Most forms of HPS and related disorders in mice result from mutations in genes that encode subunits of cytoplasmic multisubunit protein complexes involved in melanosome formation. Three of these complexes, AP-3, BLOC-1 and BLOC-2, function in trafficking distinct sets of transmembrane proteins between early endosomes and melanosomes. AP-3 is a coat protein that packages protein cargoes into endosome-derived vesicles, but the molecular functions of BLOC-1 and BLOC-2 are not known. We will exploit the genetic tools afforded by AP-3-, BLOC-1- and BLOC-2-deficient melanocytes to define endosome-to-melanosome anterograde and retrograde trafficking pathways in generalizable terms and define the molecular interactions that govern them. Preliminary evidence implicates VAMP7 and syntaxin 13, two SNARE family members that mediate membrane docking and fusion in the endosomal pathway, and the small regulatory GTPase Rab11 as functionally important in the BLOC-1 and/or AP-3 pathways. We hypothesize that BLOC-1, BLOC-2 and AP-3 function in concert with Rab11 to regulating recycling endosome membrane dynamics and SNARE-dependent membrane fusion with maturing melanosomes, and that syntaxin 13 and VAMP7 are components of the requisite SNARE complexes. We will test this general hypothesis in the following specific aims: 1. To test the hypothesis that the SNARE protein, syntaxin 13, is a component of the SNARE complex that delivers cargo to melanosomes by the BLOC-1-regulated pathway. 2. To test the hypothesis that the SNARE protein, VAMP7, is a component of the SNARE complex that links AP-3-dependent cargo delivery to melanosomes with BLOC-1-dependent cargo delivery. 3. To test the hypothesis that BLOC-2 functions in regulating SNARE-dependent fusion of early endosomal tubules with melanosomes. 4. To test the hypothesis that Rab11 effectors function as sensors of melanosome maturation by regulating the balance of anterograde and retrograde transport between endosomes and melanosomes. By defining these functions and pathways, we will further our understanding of the etiology of genetic disorders of organelle formation and provide insights into treatment regimens for HPS. PUBLIC HEALTH RELEVANCE: Hermansky-Pudlak syndrome is a group of genetic disorders that are common in Puerto Rico and are characterized by oculocutaneous albinism, excessive bleeding, and in many cases a fatal lung fibrosis and/or immune deficiency. The symptoms result from the failure to form certain specialized membrane structures, or organelles, within affected cell types. This proposal uses the melanosome, a target organelle within pigment cells, as a model system to understand how the products of the genes that are disrupted in Hermansky-Pudlak syndrome patients normally function to generate specialized organelles.
描述(由申请人提供):黑素体是组织特异性细胞内细胞器,其在眼睛色素细胞和皮肤黑素细胞中的黑素的生物合成、储存和运输中起作用。黑素体在这些细胞内通过从早期内吞细胞器有序递送特定蛋白质内容物而通过渐进发育阶段形成。黑素体形成缺陷导致眼皮肤白化病(OCA),这是一种与视力受损和皮肤和眼睛癌症易感性增强相关的疾病。OCA是与Hermansky-Pudlak综合征(HPS)相关的几种全身性疾病之一,HPS是一种遗传性疾病,其中黑素体和其他相关组织特异性细胞器无法正常形成。小鼠中大多数形式的HPS和相关疾病是由编码参与黑素体形成的细胞质多亚基蛋白复合物的亚基的基因突变引起的。这些复合物中的三种,AP-3、BLOC-1和BLOC-2,在早期内体和黑素体之间运输不同的跨膜蛋白组中起作用。AP-3是将蛋白质货物包装到内体衍生的囊泡中的外壳蛋白,但BLOC-1和BLOC-2的分子功能尚不清楚。我们将利用AP-3-,BLOC-1-和BLOC-2-缺陷黑素细胞提供的遗传工具来定义内体到黑素体的顺行和逆行运输途径,并定义控制它们的分子相互作用。初步证据表明,VAMP 7和syntaxin 13,两个SNARE家族成员,介导膜对接和融合的内体途径,和小的调节GTrib 11作为功能重要的BLOC-1和/或AP-3途径。我们假设BLOC-1,BLOC-2和AP-3与Rab 11一起调节再循环内体膜动力学和与成熟黑素体的SNARE依赖性膜融合,并且syntaxin 13和VAMP 7是必需的SNARE复合物的组分。我们将在以下具体目标中检验这一一般假设:1。为了验证SNARE蛋白,syntaxin 13,是SNARE复合物的一个组成部分,通过BLOC-1调节的途径将货物运送到黑素体的假设。2.为了检验SNARE蛋白VAMP 7是SNARE复合物的一个组分的假设,该复合物将AP-3依赖性货物递送与黑素体和BLOC-1依赖性货物递送联系起来。3.为了检验BLOC-2在调节早期内体小管与黑素体的SNARE依赖性融合中起作用的假设。4.为了验证Rab 11效应器作为黑素体成熟的传感器通过调节内体和黑素体之间的顺行和逆行运输的平衡发挥作用的假设。通过定义这些功能和途径,我们将进一步了解细胞器形成的遗传性疾病的病因,并为HPS的治疗方案提供见解。公共卫生关系:Hermansky-Pudlak综合征是一组在波多黎各常见的遗传性疾病,其特征为眼皮肤白化病、过度出血,在许多情况下,还包括致命的肺纤维化和/或免疫缺陷。这些症状是由于在受影响的细胞类型内未能形成某些专门的膜结构或细胞器。该提案使用黑素体(色素细胞内的靶细胞器)作为模型系统,以了解Hermansky-Pudlak综合征患者中被破坏的基因产物如何正常发挥作用以产生专门的细胞器。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael S Marks其他文献
Michael S Marks的其他文献
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{{ truncateString('Michael S Marks', 18)}}的其他基金
Genetic and molecular basis for variation in human skin pigmentation
人类皮肤色素沉着变化的遗传和分子基础
- 批准号:
10394237 - 财政年份:2020
- 资助金额:
$ 50.35万 - 项目类别:
Genetic and molecular basis for variation in human skin pigmentation
人类皮肤色素沉着变化的遗传和分子基础
- 批准号:
10615919 - 财政年份:2020
- 资助金额:
$ 50.35万 - 项目类别:
Mechanisms regulating ion transport across the melanosomal membrane in health and disease
在健康和疾病中调节离子跨黑素体膜运输的机制
- 批准号:
9763909 - 财政年份:2019
- 资助金额:
$ 50.35万 - 项目类别:
Mechanisms regulating ion transport across the melanosomal membrane in health and disease
在健康和疾病中调节离子跨黑素体膜运输的机制
- 批准号:
10401826 - 财政年份:2018
- 资助金额:
$ 50.35万 - 项目类别:
Mechanisms regulating ion transport across the melanosomal membrane in health and disease
在健康和疾病中调节离子跨黑素体膜运输的机制
- 批准号:
10400351 - 财政年份:2018
- 资助金额:
$ 50.35万 - 项目类别:
Mechanisms regulating ion transport across the melanosomal membrane in health and disease
在健康和疾病中调节离子跨黑素体膜运输的机制
- 批准号:
10164721 - 财政年份:2018
- 资助金额:
$ 50.35万 - 项目类别:
Platelet granule formation and function in health and disease
血小板颗粒的形成及其在健康和疾病中的功能
- 批准号:
9055752 - 财政年份:2014
- 资助金额:
$ 50.35万 - 项目类别:
Platelet granule formation and function in health and disease
血小板颗粒的形成及其在健康和疾病中的功能
- 批准号:
8703361 - 财政年份:2014
- 资助金额:
$ 50.35万 - 项目类别:
Platelet granule formation and function in health and disease
血小板颗粒的形成及其在健康和疾病中的功能
- 批准号:
8846666 - 财政年份:2014
- 资助金额:
$ 50.35万 - 项目类别:
Platelet granule formation and function in health and disease
血小板颗粒的形成及其在健康和疾病中的功能
- 批准号:
9257459 - 财政年份:2014
- 资助金额:
$ 50.35万 - 项目类别: