HEPARAN SULFATE PROTEOGLYCANS IN NEURAL DEVELOPMENT

最近的研究证明了硫酸肝素蛋白聚糖（HSPGs）在控制神经系统发育中的重要作用。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和胶原XVIII是神经组织的两种细胞外基质（ECM） HSPGs。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，因为大多数agrin的表达发生在发育中的中枢神经系统，特别是发育中的轴突束。本提案中概述的研究旨在了解agrin如何通过与神经系统中特定的ECM分子相互作用在大脑发育和衰老中起作用。本研究还将分析XVIII胶原蛋白在神经系统发育和血管生成中的功能意义。本课题的具体目标是：1)分析agrin在发育中的神经系统ECM功能中的作用。这些实验将包括验证以下假设的研究：在发育中的神经系统中，agrin和ECM蛋白之间的相互作用是细胞相互作用所必需的，并且在神经系统发育过程中，agrin在ECM的形成中起作用。2)检测正常和阿尔茨海默病脑组织中agrin及与agrin结合的ECM蛋白的表达。这些研究的基本原理是基于HSPGs可能在AD中淀粉样斑块的形成中起关键作用的假设。3)对鸡XVIII胶原蛋白进行表征，了解其在神经系统发育中的功能意义。我们最近的分子研究表明，胶原XVIII是神经系统，特别是PNS的ECM HSPG。在本课题中，我们将完成鸡XVIII胶原蛋白的分子克隆，并开始评估XVIII胶原蛋白的功能意义。特别是，我们将研究这种HSPG作为抗血管生成分子的作用。这些研究是有趣的，因为胶原XVIII的c端结构域是内皮抑素，一种已知的抗血管生成分子，也具有抗肿瘤性。最后，我们将分析XVIII胶原蛋白在中枢神经系统发育过程中血管形成中的作用。

Recent studies have documented important roles for heparan sulfate proteoglycans (HSPGs) in the control of nervous system development. 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 and collagen XVIII are two extracellular matrix (ECM) HSPGs of 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 the majority of agrin expression occurs in the developing central nervous system, especially in developing axonal tracts. The studies outlined in this proposal are aimed at understanding how agrin functions in brain development and aging by interacting with specific ECM molecules in the nervous system. The proposed studies will also analyze the functional significance of collagen XVIII in nervous system development and angiogenesis. The specific goals of this proposal are: 1) To analyze the role of agrin in ECM function in the developing nervous system. These experiments will include studies that will test the hypothesis that interactions between agrin and ECM proteins are necessary for cell interactions in the developing nervous system, and that agrin plays a role in the formation of the ECM during nervous system development. 2) To examine the expression of agrin, and ECM proteins that bind to agrin, in normal and Alzheimer's Disease brain. The rationale for these studies is based on the hypothesis that HSPGs may play a crucial role in the formation of amyloid plaques in AD. 3) To characterize chicken collagen XVIII and to understand its functional significance in the developing nervous system. Our recent molecular studies have demonstrated that collagen XVIII is an ECM HSPG of the nervous system, in particular the PNS. In the present proposal, we will complete the molecular cloning of chicken collagen XVIII and begin to assess the functional significance of collagen XVIII. In particular, we will examine the role of this HSPG as an anti-angiogenic molecule. These studies are of interest since the C-terminal domain of collagen XVIII is endostatin, a known anti-angiogenic molecule that is also anti-tumorigenic. Finally, we will analyze the role of collagen XVIII in blood vessel formation during CNS development.