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肝素蛋白聚糖（HSPGs）在神经系统衰老和发育中的重要作用。HSPGs被认为可以调节神经细胞分化、细胞粘附和阿尔茨海默病（AD）等人类疾病的发病机制等多种过程。我们实验室最近的研究表明，agrin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，因其参与神经肌肉连接处（NMJ）突触形成过程中乙酰胆碱受体（AChRs）的聚集而被识别和命名。新出现的证据表明，agrin的功能并不局限于其在突触发生中的作用，因为agrin调节轴突延伸，在成人大脑中表达，并可能与一些神经退行性疾病的病因有关。本提案中概述的研究旨在了解agrin在大脑发育和衰老中的作用机制。本课题的具体目标是：1)利用鸡和斑马鱼胚胎的体内方法，分析agin在发育中的CMS神经发生、神经模式和轴突生长中的作用。这些研究将侧重于分析agrin在调节肝素结合信号分子（如成纤维细胞生长因子（FGFs））的功能中所起的作用。研究人员将利用agin morpholino寡核苷酸敲除小鸡或斑马鱼发育过程中的agin表达，并与FGF受体功能抑制剂或FGF过表达抑制剂联合研究agin在发育过程中调控FGF信号传导中的作用。2)阐明agrin调控斑马鱼后部发育的分子机制。这些研究将验证一种假设，即通过调控FGF信号通路，agin对斑马鱼的后发发育是必要的。3)探讨agrin在AD脑β -淀粉样蛋白聚集、清除和细胞毒性调控中的作用。这些研究代表了我们的研究的延续，表明agin在调节β -淀粉样蛋白聚集中的关键作用。这些研究将包括使用AD小鼠模型来进一步研究agrin在AD中的作用。我们预测这些提出的研究将为agrin在发育和衰老的神经系统中的功能提供重要的新见解。

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.