Molecular Studies of Retinal Degeneration in Drosophila

果蝇视网膜变性的分子研究

基本信息

  • 批准号:
    8423617
  • 负责人:
  • 金额:
    $ 37.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1990
  • 资助国家:
    美国
  • 起止时间:
    1990-08-01 至 2016-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective is to understand the molecular genetics of hereditary human retinal diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Our approach is to use Drosophila as a model system. Human RP and AMD are highly complex diseases with multiple subtypes, each with a distinct genetic and biochemical basis. This complexity, along with the limited availability of suitable tissues from RP and AMD patients and the broad base of knowledge of Drosophila genetics, combine to make Drosophila a powerful animal model for studying inherited retinal degeneration disorders. Our research is focused on those events during protein biosynthesis in the secretory pathway that ensure correct protein translocation, glycosylation, folding, oligomeric assembly, quality control, transport and targeting. The endoplasmic reticulum (ER) contains a wide variety of molecular chaperones, folding sensors and enzymes, as well as escort proteins that facilitate the early stages of protein biosynthesis. Upon exiting the ER, newly folded proteins must be transported to the Golgi, where they undergo a new set of modifications that proceed sequentially from the cis- to the medial-, and finally to the trans- compartments of the Golgi. Transport of proteins between compartments of the secretory pathway occurs via the budding and fusion of small vesicles from donor compartments to target compartments. Vesicular transport is facilitated by a vast array of cytosolic and membrane bound factors, such as GTP-binding proteins (Rabs), coat components, motor proteins, tethering molecules, and finally SNAREs (soluble N- ethylmaleimide-sensitive factor attachment protein receptor). In this application we are specifically focused on two major aspects of protein biosynthesis and transport: (1) The SNARE proteins and their role in vesicular transport of rhodopsin and other constituents of phototransduction, and (2) the family of mannosidases and their key roles in trimming carbohydrates in the ER and Golgi during rhodopsin biosynthesis. Given that the SNARE proteins and mannosidase enzymes investigated here are highly conserved in humans, our findings in Drosophila should be readily applied to human processes and diseases. Accordingly, our discoveries in Drosophila will be used to screen a highly defined set of human AMD and RP pedigrees for similar defects. We anticipate that this work will greatly impact our understanding of the fundamental mechanisms of protein trafficking and also provide important insights into retinal diseases such as RP and AMD.
描述(由申请人提供):我们的长期目标是了解遗传性人类视网膜疾病的分子遗传学,如视网膜色素变性(RP)和年龄相关性黄斑变性(AMD)。我们的方法是使用果蝇作为模型系统。人类RP和AMD是具有多种亚型的高度复杂的疾病,每种亚型具有不同的遗传和生化基础。这种复杂性,沿着来自RP和AMD患者的合适组织的有限可用性以及果蝇遗传学知识的广泛基础,联合收割机使果蝇成为研究遗传性视网膜变性疾病的强大动物模型。我们的研究集中在分泌途径中蛋白质生物合成过程中的那些事件,这些事件确保正确的蛋白质易位,糖基化,折叠,寡聚体组装,质量控制,运输和靶向。内质网(ER)含有多种分子伴侣,折叠传感器和酶,以及促进蛋白质生物合成早期阶段的护送蛋白。在离开内质网后,新折叠的蛋白质必须被转运到高尔基体,在那里它们经历一系列新的修饰,这些修饰顺序地从高尔基体的顺式隔室到中间隔室,最后到反式隔室.蛋白质在分泌途径的隔室之间的转运通过小囊泡从供体隔室到靶隔室的出芽和融合而发生。囊泡转运由大量的胞质和膜结合因子促进,例如GTP结合蛋白(Rabs)、外壳组分、马达蛋白、栓系分子和最后的SNARE(可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体)。在本申请中,我们特别关注蛋白质生物合成和转运的两个主要方面:(1)SNARE蛋白及其在视紫红质和光转导的其他成分的囊泡转运中的作用,以及(2)甘露聚糖酶家族及其在视紫红质生物合成期间在ER和高尔基体中修剪碳水化合物的关键作用。考虑到SNARE蛋白和甘露糖苷酶在人类中高度保守,我们在果蝇中的发现应该很容易应用于人类的过程和疾病。因此,我们在果蝇中的发现将用于筛选一组高度定义的人类AMD和RP谱系的类似缺陷。我们预计这项工作将极大地影响我们对蛋白质运输的基本机制的理解,并为RP和AMD等视网膜疾病提供重要的见解。

项目成果

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Nansi J. Colley其他文献

ERRATUM: Vertebrate-like βγ-crystallins in the ocular lenses of a copepod

Nansi J. Colley的其他文献

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{{ truncateString('Nansi J. Colley', 18)}}的其他基金

Novel Locus Required For Photoreceptor Survival
光感受器存活所需的新位点
  • 批准号:
    6830125
  • 财政年份:
    2003
  • 资助金额:
    $ 37.63万
  • 项目类别:
Novel Locus Required For Photoreceptor Survival
光感受器存活所需的新位点
  • 批准号:
    6720309
  • 财政年份:
    2003
  • 资助金额:
    $ 37.63万
  • 项目类别:
Novel Locus Required For Photoreceptor Survival
光感受器存活所需的新位点
  • 批准号:
    6986089
  • 财政年份:
    2003
  • 资助金额:
    $ 37.63万
  • 项目类别:
Molecular Studies of Retinal Degeneration in Drosophila
果蝇视网膜变性的分子研究
  • 批准号:
    6332210
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:
Molecular Studies of Retinal Degeneration in Drosophila
果蝇视网膜变性的分子研究
  • 批准号:
    6525063
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:
MOLECULAR STUDIES OF RETINAL DEGENERATION IN DROSOPHILA
果蝇视网膜变性的分子研究
  • 批准号:
    3465821
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:
Molecular Studies of Retinal Degeneration in Drosophila
果蝇视网膜变性的分子研究
  • 批准号:
    7454182
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:
MOLECULAR STUDIES OF RETINAL DEGENERATION IN DROSOPHILA
果蝇视网膜变性的分子研究
  • 批准号:
    2162465
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:
MOLECULAR STUDIES OF RETINAL DEGENERATION IN DROSOPHILA
果蝇视网膜变性的分子研究
  • 批准号:
    3465820
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:
Molecular Studies of Retinal Degeneration in Drosophila
果蝇视网膜变性的分子研究
  • 批准号:
    6776349
  • 财政年份:
    1990
  • 资助金额:
    $ 37.63万
  • 项目类别:

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