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The role of extracellular matrix in axon routing

细胞外基质在轴突路由中的作用

基本信息

批准号：
10745085
负责人：
Reyna I Martínez-De Luna
金额：
$ 40.75万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745085
关键词：
ADGR1 gene Address Adhesions Anatomy Antibodies Axon Basement membrane Brain Brain region Cell Polarity Cells Cellular Morphology Complex Coupled Cues Data Depth Perception Development Dominant-Negative Mutation Dystroglycan Extracellular Matrix Future Goals Growth In Vitro Integrins Ipsilateral Knowledge Label Laminin Laminin Receptor Mediating Membrane Methods Microscopy Modeling Molecular Morphology Mus Neuroglia Neurons Optic Chiasm Optic tract structure PARD6A gene Pattern Phase Proliferating Proteins Radial Regulation Resolution Retinal Ganglion Cells Role Route Side Signal Transduction Spatial Distribution Surface Techniques Testing Thinness Time Tissues Vascular Endothelial Growth Factors Vision Visual System Work axon growth axon guidance axon regeneration brain cell experimental study in vivo information organization innovation insight receptor retinal axon retinal ganglion cell regeneration segregation spatiotemporal transmission process

项目摘要

Project Summary/Abstract Vision, in general, and stereopsis, in particular, depends on the selective decussation of retinal ganglion cell axons and their termination in an orderly topographic manner. Axonal decussation is directed by the radial glia and midline line neurons at the optic chiasm. The radial glia and midline neurons attach to the pial basement membrane (PBM), a cell adherent, highly organized extracellular matrix sheet that forms the basal surface of the brain including the chiasm. A key component of the PBM are laminins. In other brain regions laminins containing the 2 subunit (2 laminins) provide environmental cues that control tissue and cellular organization including polarity, proliferation, and differentiation. We hypothesize that 2 laminins in the PBM of the chiasm function to polarize the radial glia and midline neurons. This polarization, in turn, regulates the spatial organization of guidance cues thereby regulating axon decussation. Consistent with this hypothesis, we found that loss of 2 laminins from the PBM decreased axonal decussation resulting in an increased ipsilateral projection. We will critically test this hypothesis in three aims. In Aim 1 we will determine the role of 2 laminins in the control of axonal guidance cue expression during the early, peak, and late phases of axon growth. In Aim 2, we will determine which laminin receptors are required for the polarity of radial glial cells and axon decussation using a combination of in vivo and in vitro approaches. Our in vivo experiments will employ cell specific deletion of laminin receptors, while our in vitro experiments will employ a technically innovative organotypic approach using function blocking techniques. In Aim 3, we will determine how 2 laminins control the radial glia and midline neuron cell polarity using sparse labeling of the cells and high-resolution microscopy. The experiments proposed here will define the role of the β2 laminins during optic chiasm and tract formation. The findings from this work will pave the way to exploit cell-matrix interactions for the development of rational strategies to promote the guided growth and decussation of regenerating retinal ganglion cell axons.

项目概要/摘要一般来说，视觉，特别是立体视觉，取决于视网膜神经节细胞的选择性交叉轴突及其以有序的地形方式终止。轴突交叉由放射状胶质细胞引导和视交叉处的中线神经元。放射状胶质细胞和中线神经元附着在软脑膜基底上膜（PBM），一种细胞粘附的、高度组织化的细胞外基质片，形成细胞的基底表面大脑，包括交叉。 PBM 的一个关键组成部分是层粘连蛋白。在其他大脑区域中含有层粘连蛋白 2 亚基（2 层粘连蛋白）提供控制组织和细胞组织的环境线索，包括极性、增殖和分化。我们假设交叉功能的 PBM 中的 2 层粘连蛋白极化放射状胶质细胞和中线神经元。这种极化反过来又调节了空间组织引导线索从而调节轴突交叉。与这个假设一致，我们发现 2 的损失来自 PBM 的层粘连蛋白减少了轴突交叉，导致同侧投射增加。我们将从三个目标中批判性地检验这一假设。在目标 1 中，我们将确定 2 层粘连蛋白在控制轴突生长的早期、高峰和晚期阶段的轴突引导线索表达。在目标 2 中，我们将确定放射状胶质细胞的极性和轴突交叉所需的层粘连蛋白受体体内和体外方法的结合。我们的体内实验将采用层粘连蛋白的细胞特异性删除受体，而我们的体外实验将采用一种技术创新的器官型方法，利用功能阻塞技术。在目标 3 中，我们将确定 2 层粘连蛋白如何控制放射状胶质细胞和中线神经元细胞使用细胞的稀疏标记和高分辨率显微镜来确定极性。这里提出的实验将定义 β2 层粘连蛋白在视交叉和视束形成过程中的作用。这项工作的结果将为利用细胞-基质相互作用来制定促进引导生长的合理策略的方法以及再生视网膜神经节细胞轴突的交叉。