Heparan sulfate proteoglycans in aging and development

描述(由申请人提供)：最近的研究证明了硫酸乙酰肝素蛋白多糖(HSPGs)在神经系统老化和发育中的重要作用。HSPGs被认为可以调节神经细胞分化、细胞黏附以及阿尔茨海默病(AD)等人类疾病的发病机制。我们实验室最近的研究表明，集聚蛋白是神经组织中主要的细胞外基质(ECM)和跨膜HSPG。AGRIN是一种细胞外基质蛋白，根据其在神经肌肉接头(NMJ)突触发生过程中参与乙酰胆碱受体(AChRs)聚集而被识别和命名。新的证据表明，集聚蛋白的功能不仅限于其在突触发生中的作用，因为集聚蛋白调节轴突的延伸，在成人脑中表达，并可能与一些神经退行性疾病的病因有关。这项提案中概述的研究旨在了解集聚蛋白在大脑发育和衰老中发挥作用的机制。这项建议的具体目标是：1)利用活体方法在鸡和斑马鱼胚胎中分析集聚蛋白在发育中的CMS中的神经发生、神经模式形成和轴突生长中的作用。这些研究将集中于分析集聚蛋白在调节肝素结合的信号分子如成纤维细胞生长因子(FGFs)的功能中所起的作用。在鸡或斑马鱼的发育过程中，agrin将被用来下调agrin的表达，并将与成纤维细胞生长因子受体功能的抑制剂或成纤维细胞生长因子的过度表达结合，以探讨agrin在发育过程中对成纤维细胞生长因子信号的调控作用。2)阐明集聚蛋白调控斑马鱼后天发育的分子机制。这些研究将检验这一假说，即集聚蛋白通过调节成纤维细胞生长因子信号通路，对斑马鱼的后天发育是必要的。3)探讨集聚蛋白对AD大鼠脑内β-淀粉样蛋白聚集、清除和细胞毒性的调节作用。这些研究是我们研究的继续，表明集聚蛋白在调节β-淀粉样蛋白聚集中起着关键作用。这些研究将包括使用AD小鼠模型进一步研究集聚蛋白在AD中的作用。我们预测，这些拟议的研究将为集聚蛋白在神经系统发育和老化中的作用提供重要的新见解。

DESCRIPTION (provided by applicant): Recent studies have documented important roles for heparan sulfate proteoglycans (HSPGs) in aging and development of the nervous system. HSPGs are proposed to regulate processes as diverse as neural cell differentiation, cell adhesion, and the pathogenesis of human diseases such as Alzheimer's disease (AD). Recent studies from our laboratories have shown that agrin is a major extracellular matrix (ECM) and transmembrane HSPG in nervous tissue. Agrin is an extracellular matrix protein identified and named based on its involvement in the aggregation of acetylcholine receptors (AChRs) during synaptogenesis at the neuromuscular junction (NMJ). Emerging evidence indicates that agrin's function is not limited to its role in synaptogenesis, as agrin modulates axon extension, is expressed in adult brain, and may contribute to the etiology of some neurodegenerative diseases. The studies outlined in this proposal are aimed at understanding mechanisms by which agrin functions in brain development and aging. The specific goals of this proposal are: 1) To analyze the role of agrin in neurogenesis, neural patterning and axonal growth in the developing CMS, using in vivo approaches in chicken and zebrafish embryos. These studies will focus on analyzing the role agrin plays in modulating the function of heparin-binding signaling molecules such as the fibroblast growth factors (FGFs). Agrin morpholino oligonucleotides will be employed to knock-down agrin expression during chick or zebrafish development, and will be combined with inhibitors of FGF receptor function or FGF overexpression to explore agrin's role in the modulation of FGF signaling during development. 2) To elucidate the molecular mechanisms by which agrin regulates posterior development in zebrafish. These studies will test the hypothesis that agrin, via regulation of FGF signaling pathways, is necessary for posterior development in zebrafish. 3) To examine the role of agrin in the regulation of beta-amyloid aggregation, clearance and cytotoxicity in AD brain. These studies represent a continuation of our studies that suggest a crucial role for agrin in modulating beta-amyloid aggregation. These studies will include the use of AD mouse models to investigate further the role of agrin in AD. We predict that these proposed studies will provide important new insight into the function of agrin in the developing and aging nervous system.