EXTRACELLULAR MATRIX IN SYNAPSE FORMATION IN THE CNS
中枢神经系统突触形成中的细胞外基质
基本信息
- 批准号:6384826
- 负责人:
- 金额:$ 27.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-08-01 至 2003-07-31
- 项目状态:已结题
- 来源:
- 关键词:animal tissue central nervous system confocal scanning microscopy electrophysiology extracellular matrix gene targeting genetically modified animals immunocytochemistry in situ hybridization laboratory mouse laminin organ culture protein structure function receptor binding retina retina degeneration retinal bipolar neuron rod cell synaptogenesis visual photoreceptor
项目摘要
DESCRIPTION (Verbatim from applicant's abstract): Laminins are
biologically-active molecules which function as cell adhesion molecules,
regulate various aspects of development, and serve to stabilize complex
anatomical structures. They are large extracellular matrix molecules that are
composed of three subunit chains, designated alpha, beta and gamma. Five alpha,
three beta and three gamma chains have been identified. Several disorders of
the nervous system are linked to laminin genes: some congenital muscular
dystrophies involve the alpha2 chain (merosin); the beta2 chain is reduced in
Walker-Warburg syndrome, and a complex group of CNS developmental disorders
(muscle-brain-eye disease; retinitis pigmentosa with deafness (RP21 with
deafness); Walker-Warburg syndrome) map to the site of the gamma3 gene.
Laminins are widely expressed in the CNS; we have shown that in the human, rat,
bovine and mouse retina, four laminin chains (alpha3, alpha4, beta2 and gamma3)
are found in the interphotoreceptor matrix and in the matrix of the outer
plexiform layer (OPL). These chains are likely to form two heterotrimers,
laminin-13 and laminin-14. The retinal laminin chains appear to play important
roles in the morphogenesis of photoreceptors; first, these chains are expressed
prior to the onset of rod genesis and persist into adulthood; second, ablation
of the gene encoding one of the chains, beta2, results in the production of
dysmorphic photoreceptors with aberrant function. Specifically, photoreceptor
outer segments are reduced in length; the photoreceptor terminal in the OPL are
disrupted: finally, in ERGs, the amplitude of the b-wave is drastically
diminished, suggesting that transmission between photoreceptors and bipolar
cells is disrupted by loss of laminin beta2 chain function. We hypothesize that
laminins-13 and -14 are critical mediators of synapse formation and
stabilization between photoreceptors and second order cells in the OPL.
Furthermore, we hypothesize that laminins-13 and -14 form unique substrates
with which photoreceptor axons interact and to which they adhere in order to
elaborate synapses, and, finally, that the molecular structure of the synapse
is dependent on the interactions between these laminins and their receptors. We
propose to test several aspects of this hypothesis. We will ask several
specific questions: (1) what the spatial and temporal expression of
laminin-binding molecules is in the OPL; (2) whether these molecules mediate
the binding of cells to OPL laminins; and (3) what anatomical and physiological
alterations in the photoreceptor synapse result from laminin gene disruptions.
描述(逐字摘自申请者摘要):层粘连蛋白是
作为细胞黏附分子的生物活性分子,
规范各方面发展,服务于稳定复合体
解剖结构。它们是大的细胞外基质分子,
由三个亚单位链组成,分别命名为α、β和伽马。五个阿尔法,
已经确定了三条贝塔和三条伽马链。几种精神障碍
神经系统与层粘连蛋白基因有关:一些先天性肌肉
营养不良涉及Alpha2链(Merosin);Beta2链在
Walker-Warburg综合征和一组复杂的中枢神经系统发育障碍
(肌肉-脑-眼疾病;伴有耳聋的视网膜色素变性(RP21)
耳聋);Walker-Warburg综合征)定位于Gamma3基因的位置。
层粘连蛋白广泛表达于中枢神经系统;我们已经证明,在人、大鼠、
牛和小鼠视网膜,四条层粘连蛋白链(α3、α4、β2和γ3)
在光感受器之间的基质中和在外部的基质中
丛状层(OPL)。这些链可能形成两个杂三聚体,
层粘连蛋白-13和层粘连蛋白-14。视网膜层粘连蛋白链似乎扮演着重要的角色
在光感受器的形态发生中的作用;首先,这些链被表达
在杆状突起之前并持续到成年期;第二,消融
编码其中一条链Beta2的基因导致产生
具有异常功能的变形光感受器。具体地说,光感受器
外节的长度减少;OPL中的光感受器末端是
干扰:最后,在ERG中,b波的幅度急剧下降。
减弱,表明光感受器和双相之间的传输
细胞受到层粘连蛋白β2链功能丧失的干扰。我们假设
层粘连蛋白-13和-14是突触形成和
OPL中光感受器和二级细胞之间的稳定。
此外,我们假设层粘连蛋白-13和-14形成独特的底物
光感受器轴突与之相互作用并附着于其上,以便
精致的突触,最后,突触的分子结构
依赖于这些层粘连蛋白和它们的受体之间的相互作用。我们
建议对这一假设的几个方面进行检验。我们会问几个
具体问题:(1)什么是空间和时间表达
层粘连蛋白结合分子在OPL中;(2)这些分子是否参与
细胞与OPL层粘连蛋白的结合;以及(3)什么解剖学和生理学
光感受器突触的改变是层粘连蛋白基因破坏的结果。
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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WILLIAM J BRUNKEN其他文献
WILLIAM J BRUNKEN的其他文献
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{{ truncateString('WILLIAM J BRUNKEN', 18)}}的其他基金
Role of Extracellular Matrix in Retinal Development and Disease
细胞外基质在视网膜发育和疾病中的作用
- 批准号:
10330943 - 财政年份:2019
- 资助金额:
$ 27.74万 - 项目类别:
Role of Extracellular Matrix in Retinal Development and Disease
细胞外基质在视网膜发育和疾病中的作用
- 批准号:
8512409 - 财政年份:2000
- 资助金额:
$ 27.74万 - 项目类别:
Extracellular matrix in synapse formation in the CNS
中枢神经系统突触形成中的细胞外基质
- 批准号:
6929077 - 财政年份:2000
- 资助金额:
$ 27.74万 - 项目类别:
Role of Extracellular Matrix in Retinal Development and Disease
细胞外基质在视网膜发育和疾病中的作用
- 批准号:
7992716 - 财政年份:2000
- 资助金额:
$ 27.74万 - 项目类别:
EXTRACELLULAR MATRIX IN SYNAPSE FORMATION IN THE CNS
中枢神经系统突触形成中的细胞外基质
- 批准号:
6446640 - 财政年份:2000
- 资助金额:
$ 27.74万 - 项目类别:
STRUCTURE AND FUNCTION OF NON BASEMENT MEMBRANE LAMININS
非基底膜层粘连蛋白的结构和功能
- 批准号:
6499449 - 财政年份:2000
- 资助金额:
$ 27.74万 - 项目类别:
Extracellular matrix in synapse formation in the CNS
中枢神经系统突触形成中的细胞外基质
- 批准号:
7087782 - 财政年份:2000
- 资助金额:
$ 27.74万 - 项目类别:
Extracellular matrix in synapse formation in the CNS
中枢神经系统突触形成中的细胞外基质
- 批准号:
7251457 - 财政年份:2000
- 资助金额:
$ 27.74万 - 项目类别:
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