Quality control mechanisms against misfolded rhodopsins in Drosophila.
Quality control mechanisms against misfolded rhodopsins in Drosophila.
批准号:
8301711
负责人:
HYUNG D RYOO
金额:
$33.8万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-08-01 至 2014-07-31
关键词:
AffectAge-YearsAllelesAmino Acid SubstitutionAnimal ModelAttentionBindingBiologicalBiological AssayBlindnessCellsCytoplasmDevelopmentDiseaseDrosophila genusEmployee StrikesEndoplasmic ReticulumEndoplasmic Reticulum Degradation PathwayGene DosageGene ExpressionGenesGeneticGenetic TranscriptionGoalsHereditary DiseaseHomologous GeneHumanInborn Genetic DiseasesIndividualLongevityMammalian CellMediatingMessenger RNAModelingMutationOutcome StudyPathway interactionsPhosphoric Monoester HydrolasesPhosphorylationProcessPropertyProtein DephosphorylationProteinsQuality ControlRNA BindingRNA InterferenceRNA Recognition MotifRNA SplicingRegulationRetinaRetinalRetinal DegenerationRetinitis PigmentosaRhodopsinRoleSignal PathwaySignal TransductionStressTestingTherapeuticUbiquitinYeastsabstractingage relatedendonucleaseendoplasmic reticulum stressflygenome-widehigh throughput analysisinsightinterestmulticatalytic endopeptidase complexmutantnovelnovel therapeuticsoverexpressionphosphatase inhibitorprotective effectprotein complexprotein foldingprotein misfoldingresponsetooltranscription factor
中文摘要
项目摘要/摘要
视网膜色素变性是一组遗传性疾病,表现为视网膜功能的进行性丧失。其中之一
常染色体显性遗传性视网膜色素变性(ADRP)最常见的原因是视紫红质基因突变
破坏其编码蛋白质折叠特性的基因。我们的长期目标是了解细胞如何反应
一旦这些视紫红质蛋白在内质网(ER)中合成,就会产生应激反应。AS
大多数细胞都有强大的质量控制机制,可以帮助将这些错误折叠的蛋白质从
呃,更好地了解这些机制可能会有治疗意义。我们的重点是两个具体的
ER质量控制机制,可帮助抑制错误折叠的视紫红质引起的视网膜退化。
首先是内质网相关降解(ERAD),它指的是泛素介导的错误折叠的降解
来自急诊室的蛋白质。刺激ERAD可以抑制ADRP果蝇模型的视网膜退化,
但人们对其潜在机制仍知之甚少。此外,ADRP可能被一种
内质网应激激活的细胞内信号通路称为未折叠蛋白反应(UPR)。一个
UPR的中心分支是由XBP1 mRNA在细胞质中的非常规剪接介导的,导致
目的在于合成具有活性的XBP1转录因子。XBP1的转录靶点包括
ERAD的监管机构。探讨ERAD和UPR抑制大鼠视网膜变性的机制
ADRP的动物模型,我们计划结合经典的果蝇遗传学、细胞生物学分析
和高通量RNAi检测。具体地说,我们计划调查通过什么机制
错误折叠的视紫红质由ERAD机器检测并输入细胞质进行降解。在……里面
此外,我们计划研究XBP1介导的UPR途径是如何调控的。我们将检验一个特定的假设
其中XBP1的mRNA剪接受一种特定的磷酸酶调节,而该磷酸酶又受调节
通过与XBP1 mRNA结合的调节亚基。通过这个发现的任何新的基因或机制
将研究adrp对果蝇模型视网膜退行性变的可能影响。
视紫红质编码基因的内源性突变引发年龄相关性视网膜的显性改变
退化。由于苍蝇模型显示出与人类状况惊人的相似程度,我们认为
这项研究的成功结果可能直接影响抗ADRP新策略的制定。
人类。
英文摘要
Project Summary/Abstract
Retinitis Pigmentosa is a group of inherited disorders that show a progressive loss of retinal function. One of
the most common causes of Autosomal Dominant Retinitis Pigmentosa (ADRP) are mutations in the rhodopsin
gene that disrupt its encoded protein's folding property. Our long-term goal is to understand how cells respond
to stress caused by such rhodopsin proteins once they are synthesized in the endoplasmic reticulum (ER). As
most cells have robust quality control mechanisms that can help eliminate such misfolded proteins from the
ER, a better understanding of these mechanisms may have therapeutic implications. We focus on two specific
ER quality control mechanisms that can help suppress retinal degeneration caused by misfolded rhodopsins.
First is ER-Associated Degradation (ERAD), which refers to the ubiquitin-mediated degradation of misfolded
proteins from the ER. Stimulation of ERAD can suppress retinal degeneration in a Drosophila model for ADRP,
but the underlying mechanism remains poorly understood. In addition, ADRP may be suppressed by an
intracellular signaling pathway activated by ER-stress, known as the Unfolded Protein Response (UPR). A
central branch of the UPR is mediated by the unconventional splicing of xbp1 mRNA in the cytoplasm, leading
to the synthesis of an active xbp1 transcription factor. Among the transcription targets of xbp1 include
regulators of ERAD. To investigate mechanisms by which ERAD and the UPR suppress retinal degeneration in
animal models of ADRP, we plan to use a combination of classical Drosophila genetics, cell biological analysis
and high throughput RNAi assays. Specifically, we plan to investigate the precise mechanism by which
misfolded rhodopsins are detected by the ERAD machinery and imported into the cytoplasm for degradation. In
addition, we plan to study how the xbp1-mediated UPR pathway is regulated. We will test a specific hypothesis
where xbp1 mRNA splicing is modulated by a specific phosphatase, and this phosphatase is in turn regulated
by a regulatory subunit that binds to xbp1 mRNA. Any new genes or mechanisms identified through this
approach will be examined for possible effects on retinal degeneration in a Drosophila model for ADRP, where
an endogenous mutation in a rhodopsin encoding gene triggers a dominant form of age-related retinal
degeneration. As the fly model shows a striking degree of similarity with the human condition, we believe that a
successful outcome of this study may directly influence the development of new strategies against ADRP in
humans.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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海外基金