The role of connexin32 in the pathogenesis of CMTX
Connexin32在CMTX发病机制中的作用
基本信息
- 批准号:7213822
- 负责人:
- 金额:$ 30.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-02-01 至 2010-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAstrocytesBiological ModelsBrainCell DeathCell membraneCellsCharcot-Marie-Tooth DiseaseClinicalCo-ImmunoprecipitationsComplexConnexin 43ConnexinsConnexonCoupledCouplingDefectDiffusionDiseaseDominant-Negative MutationDyesElectrophysiology (science)Endoplasmic ReticulumFluorescence Resonance Energy TransferGap JunctionsGene FamilyGenesGolgi ApparatusGrantGreen Fluorescent ProteinsHela CellsHumanIndividualIonsKnockout MiceLabelLinkMagnetic Resonance ImagingMammalsMediatingMolecularMusMutant Strains MiceMutationMyelinNatureOligodendrogliaPathogenesisPatientsPelizaeus-Merzbacher DiseasePhenotypeProteinsPublishingRelative (related person)Research PersonnelRoleSliceSpastic ParaparesisSpinal CordSyndromeVertebratesWild Type Mousedysmyelinationgap junction channelintracellular protein transportmolecular massmutantoculodentodigital dysplasiaprogramsprotein transportsmall moleculetraffickingwhite matter
项目摘要
DESCRIPTION (provided by applicant): Mutations in GJB1, GJA1, and GJA12, the genes that encode human connexin32 (hCx32), hCx43, and hGx47, cause the X-linked form of Charcot-Marie-Tooth disease (CMT1X), oculodentodigital dysplasia (ODDD), and Pelizaeus-Merzbacher-like disease (PMLD), respectively, all of which cause important CNS abnormalities that appear to be related to abnormal functioning of oligodendrocytes. The central theme of this grant is that Cx30:Cx32 and Cx43:Cx47 heterotypic channels mediate astrocyte/oligodendrocyte (A/O) coupling, which is disrupted by mutations of GJB1/Cx32, GJA1/Cx43, or GJA12/Cx47.
1. Investigate the molecular defects of hCx47 mutants causing PMLD. We will characterize further the nature of these defects, and determine whether wild type (WT) hCx47 or these hCx47 mutants can form functional channels with hCx43 by dye transfer and electrophysiology.
2. Investigate the molecular defects of hCx43 mutants causing ODDD.
We will investigate the molecular nature of the mutants proteins, determine whether cells expressing an ODDD mutant can form functional channels by themselves, or with cells expressing either WT hCx43 or WT hCx47, and determine whether ODDD mutants' have dominant-negative effects on-WT hCx43.
3. Determine whether hCx32 "CNS mutants" have dominant effects on hCx47.
In HeLa cells these "CNS mutants" accumulate either in the endoplasmic reticulum (ER) or in the Golgi. Our preliminary evidence indicates that co-expression of these "CNS mutants" with WT hCx47 results in partial retention of Wt hCx47 in the ER or Golgi, indicating that these Cx32 mutants exert a dominant effect on WT hCx47. We will characterize further the nature of these defects.
4. Determine the role of Cx32 and Cx47 in astrocyte/oligodendrocyte coupling.
We will immunostain the brains of mice that lack Cx32 and/or Cx47, and determine whether the localization of their proposed partners is altered. We will also investigate A/O coupling by injecting astrocytes genetically labeled with green fluorescent protein (GFP) in acute spinal cord slices from Gjb1/cx32 and Gja12/cx47 double null" mice with small molecules that can cross GJs. In this way, we will determine the relative importance of the two kinds of heterotypic channels in A/0 coupling.
描述(申请人提供):编码人类连接蛋白32(hCx 32)、hCx 43和hGx 47的基因GJB 1、GJA 1和GJA 12的突变分别导致X连锁型腓骨肌萎缩症(CMT 1X)、眼齿指发育不良(ODDD)和Pelizaeus-Merzbacher样疾病(PMLD),所有这些都引起似乎与少突胶质细胞功能异常有关的重要CNS异常。这项资助的中心主题是Cx 30:Cx 32和Cx43:Cx47异型通道介导星形胶质细胞/少突胶质细胞(A/O)偶联,其被GJB 1/Cx 32,GJA 1/Cx43或GJA 12/Cx47的突变破坏。
1.研究导致PMLD的hCx 47突变体的分子缺陷。我们将进一步表征这些缺陷的性质,并确定野生型(WT)hCx 47或这些hCx 47突变体是否可以通过染料转移和电生理学与hCx 43形成功能通道。
2.研究引起ODD的hCx 43突变体的分子缺陷。
我们将研究突变体蛋白的分子性质,确定表达ODDD突变体的细胞是否可以自身形成功能通道,或者与表达WT hCx 43或WT hCx 47的细胞形成功能通道,并确定ODDD突变体是否对WT hCx 43具有显性负效应。
3.确定hCx 32“CNS突变体”是否对hCx 47具有显性效应。
在HeLa细胞中,这些“CNS突变体”积聚在内质网(ER)或高尔基体中。我们的初步证据表明,这些“CNS突变体”与WT hCx 47的共表达导致WT hCx 47在ER或高尔基体中的部分保留,表明这些Cx 32突变体对WT hCx 47发挥显性作用。我们将进一步描述这些缺陷的性质。
4.确定Cx 32和Cx47在星形胶质细胞/少突胶质细胞偶联中的作用。
我们将对缺乏Cx 32和/或Cx47的小鼠的大脑进行免疫染色,并确定其拟议伴侣的定位是否改变。我们还将研究A/O偶联,方法是将绿色荧光蛋白(GFP)基因标记的星形胶质细胞注射到Gjb 1/cx 32和Gja 12/cx 47双无效”小鼠的急性脊髓切片中,并注射可以穿过GJ的小分子。通过这种方式,我们将确定两种异型通道在A/0偶联中的相对重要性。
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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STEVEN Simon Scherer其他文献
STEVEN Simon Scherer的其他文献
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{{ truncateString('STEVEN Simon Scherer', 18)}}的其他基金
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How do dominant PMP2 mutations cause demyelinating neuropathy?
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How do dominant PMP2 mutations cause demyelinating neuropathy?
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- 资助金额:
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The Role of Connexin32 in the Pathogensis of CMTX
Connexin32在CMTX发病机制中的作用
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8337714 - 财政年份:2007
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$ 30.84万 - 项目类别:
The Role of Connexin32 in the Pathogensis of CMTX
Connexin32在CMTX发病机制中的作用
- 批准号:
8186867 - 财政年份:2007
- 资助金额:
$ 30.84万 - 项目类别:
The Role of Connexin32 in the Pathogensis of CMTX
Connexin32在CMTX发病机制中的作用
- 批准号:
8732705 - 财政年份:2007
- 资助金额:
$ 30.84万 - 项目类别:
The role of connexin32 in the pathogenesis of CMTX
Connexin32在CMTX发病机制中的作用
- 批准号:
7342822 - 财政年份:2007
- 资助金额:
$ 30.84万 - 项目类别:
The role of connexin32 in the pathogenesis of CMTX
Connexin32在CMTX发病机制中的作用
- 批准号:
7730833 - 财政年份:2007
- 资助金额:
$ 30.84万 - 项目类别:
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