VEGF regulation of neurogenesis

描述（由申请人提供）：本工作的总体目标是表征发育过程中调节神经和血管细胞相互作用的细胞和分子机制。这项工作的中心目标是确定血管内皮生长因子（VEGF）在调节神经发生中的作用。这项研究的结果将影响我们对中枢神经系统（CNS）发育以及CNS对机械损伤或病理性应激反应的可塑性的理解。神经和血管系统的发展是一致的，已经确定了几个因素在两个系统中具有重叠的功能。一个新兴的模型，神经和血管系统的相互依赖性，包括有效的血管生成因子，VEGF，其双重作用，作为一个神经调节。VEGF的血管生成诱导作用主要是通过激活VEGF受体-2（VEGFR 2）同型二聚体介导的，该同型二聚体可以使用共受体神经纤毛蛋白1。神经纤毛蛋白1在介导轴突导向信号中起关键作用，但也可以通过其与VEGFR 2的结合促进血管生成。VEGF在小鼠中主要表达为三种同种型，VEGF 120、VEGF 164和VEGF 188。小鼠同源重组研究的结果表明不同的VEGF亚型具有不同的作用。同种型的不同之处在于它们与基质中和细胞表面上的硫酸乙酰肝素蛋白聚糖结合的能力以及与神经纤毛蛋白1共受体相互作用的能力。只有VEGF 164被证明可以结合并激活VEGFR 2/神经纤毛蛋白1复合物。VEGF 164是脑中的主要同种型。虽然许多研究表明VEGF在神经系统中的作用，但对VEGF在神经发生中的直接作用知之甚少。该提议的假设是VEGF通过VEGFR 2-neuropilin途径调节发育神经发生。将以以下目的检验该假设：1）表征CNS中发育神经发生期间VEGF、VEGFR 2和活化的VEGFR 2的细胞类型特异性和表达模式，和2）测试VEGF-神经纤毛蛋白信号传导在缺乏VEGF-神经纤毛蛋白信号传导的小鼠中发育神经发生中的作用。 项目叙述：该提案中描述的实验结果与大脑发育，功能和修复领域的人类健康直接相关。神经干细胞是所有脑神经元的来源，最近在成人中发现。了解神经干细胞如何产生，分化，分裂和死亡可能是找出如何在使人衰弱的CNS损伤（如中风，病变和神经退行性疾病）后恢复脑功能的关键。

DESCRIPTION (provided by applicant): The overall goal of the present work is to characterize the cell and molecular mechanisms that regulate neural and vascular cell interactions during development. The central objective of this work is to determine the role of vascular endothelial growth factor (VEGF) in regulation of neurogenesis. Results from the proposed study will impact our understanding of the development of the central nervous system (CNS) as well as the plasticity of the CNS in response to mechanical injury or pathologic stress. Neural and vascular systems develop in concert and several factors have been identified with overlapping function in the two systems. An emerging model of neural and vascular system interdependence includes the potent angiogenesis factor, VEGF, and its dual role as a neural regulator. The angiogenesis-inducing effects of VEGF are largely mediated via activation of the VEGF receptor-2 (VEGFR2) homodimer that can use the co-receptor, neuropilin 1. Neuropilin 1 plays a critical role in mediating axon guidance cues, but can also contribute to angiogenesis via its association with VEGFR2. VEGF is expressed predominantly as three isoforms in the mouse, VEGF120, VEGF164 and VEGF188. Results from homologous recombination studies in mice have led to the suggestion of distinct roles for the different VEGF isoforms. The isoforms differ in their ability to bind to heparan sulfate proteoglycans in the matrix and on the cell surface and to interact with the neuropilin 1 co-receptor. Only VEGF164 has been shown to bind to and activate the VEGFR2/neuropilin 1 complex. VEGF164 is the predominant isoform in the brain. Although a number of studies have suggested a role for VEGF in the nervous system, little is known about the direct role that VEGF plays in neurogenesis. The hypothesis of this proposal is that VEGF regulates developmental neurogenesis via the VEGFR2-neuropilin pathway. The hypothesis will be tested with the following aims: 1) to characterize the cell-type specificity and expression patterns for VEGF, VEGFR2 and activated VEGFR2 during developmental neurogenesis in the CNS and 2) to test the role of VEGF-neuropilin signaling in developmental neurogenesis in mice lacking VEGF-neuropilin signaling. Project Narrative: The results from experiments described in this proposal are directly relevant to human health in the areas of brain development, function, and repair. Neuronal stem cells are the source of all brain neurons and have recently been found in the adult. Understanding how neural stem cells arise, differentiate, divide and die may be the key to finding out how to restore brain function after debilitating CNS injuries such as stroke, lesion, and neurodegenerative disease.