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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

基本信息

批准号：
10330943
负责人：
WILLIAM J BRUNKEN
金额：
$ 15.04万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330943
关键词：
Ablation Address Affect Animals Apical Astrocytes Autoimmune Diseases Blindness Blood Vessels Brain Cell Cycle Cell Cycle Regulation Cells Congenital Abnormality Cues Data Development Disease Disseminated Malignant Neoplasm Endothelial Cells Endothelium Extracellular Matrix Eye Funding Genes Genetic Glaucoma Gliosis Goals Human Inheritance Patterns Laminin Lead Life Measures Mediating Mental Retardation Microglia Muller&apos s cell Mus Mutation Pattern Photoreceptors Play Proliferative Vitreoretinopathy Protein Isoforms Publishing Radial Regulation Retina Retinal Ganglion Cells Role Signal Transduction Synapses System Vascularization Visual impairment Work angiogenesis autism spectrum disorder design experimental study genetic approach human disease improved kidney dysfunction migration neovascular neurogenesis novel diagnostics novel therapeutics preservation progenitor recruit retinal progenitor cell reverse genetics three dimensional cell culture three dimensional structure

项目摘要

Contact PD/PI: Brunken, William, J. The immediate goal of our project is to understand the role of the extracellular matrix in retinal development and disease. In prior funding periods, we identified unique isoforms of laminins, containing either the β2 or γ3 chains that are expressed in the eye and brain. Mutations in these two laminin genes, in humans, result in autism, ocular dysgenesis, and kidney dysfunction. Ablation of these genes, in mouse, produce cortical and ocular dysgenesis; the latter includes disruptions of: 1) retinal ganglion cell development; 2) astrocyte migration and subsequent vascular development; 3) the sub-cellular organization of the Müller cell; 4) the photoreceptor- bipolar synapse. Our fundamental hypothesis is that laminins are critical for establishing the three dimensional structure of the retina. Specifically, we hypothesize that laminins provide environmental cues that are essential for angiogenesis and neurogenesis. Our first aim explores the contributions of laminin signaling in formation of the template for angiogenic development. The working hypothesis is that RGCs drive astrocyte migration; then, interactions between astrocytes and microglia regulate endothelial development. We will use a reverse genetic approach, deleting Lamb2 or Lamc3 genes alone, or together, to disrupt the signaling among these cells. The first set of experiments will focus on the spatial patterning in Lamb2-/- and Lamc3-/- animals. Our second set of experiments will address the role of laminin-mediated recruitment and activation of microglia. The third set of experiments will examine the effectors of laminin signaling in endothelial cells during angiogenesis. Our current data suggest that β2-containing laminins are pro-angiogenic and γ3-containing laminins are anti-angiogenic. Our second aim is focused on the role of laminins in neurogenesis. We will examine the hypothesis that laminin regulates apical-basal polarity of the radially organized progenitor. Our published data demonstrate that Müller cell compartmentalization is disrupted in the Lamb2-/- retina. Moreover, our preliminary data demonstrate that the cell cycle is dysregulated in both Lamb2-/- and Lamc3-/- mice. Our first set of experiments will focus on the regulation of symmetric versus asymmetric division in the Lamb2-/- and Lamc3-/- retina. Next, we will turn to a study of the pattern of inheritance of important cell cycle regulators in these same mice. Last, we will measure directly the cell cycle regulation in Lamb2-/- and Lamc3-/- retina. Our preliminary data suggest that β2- and γ3-containing laminins are necessary to preserve the proliferative state. Our work is relevant to an understanding of the pathobiology of retinal neovascular disease, gliosis and proliferative vitreoretinopathy because astrocytes and microglia play critical roles in retinal vascularization and remodeling. Our work on retinal progenitor cells will improve our fundamental understanding of retinal development and our understanding of the regulation of the cell cycle in CNS progenitors and will influence the development of 3D culture systems designed to grow retina ex vivo. Project Summary/Abstract Page 6

联系PD/PI: Brunken， William， J。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of two novel activities of the Wnt signaling regulator Dickkopf 3 and characterization of its expression in the mouse retina.

DOI：
10.1186/1471-2121-8-52
发表时间：
2007-12-19
期刊：
BMC cell biology
影响因子：
0
作者：
Nakamura RE;Hunter DD;Yi H;Brunken WJ;Hackam AS
通讯作者：
Hackam AS

Lack of netrin-4 modulates pathologic neovascularization in the eye.

DOI：
10.1038/srep18828
发表时间：
2016-01-06
期刊：
Scientific reports
影响因子：
4.6
作者：
Kociok N;Crespo-Garcia S;Liang Y;Klein SV;Nürnberg C;Reichhart N;Skosyrski S;Moritz E;Maier AK;Brunken WJ;Strauß O;Koch M;Joussen AM
通讯作者：
Joussen AM

Extracellular Matrix Components Regulate Cellular Polarity and Tissue Structure in the Developing and Mature Retina.