VEGF regulation of neurogenesis

描述（由申请人提供）：目前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）发育的理解，以及中枢神经系统在机械损伤或病理性应激下的可塑性。神经系统和血管系统是协同发展的，已经确定了几个因素在两个系统中具有重叠的功能。一个新兴的神经和血管系统相互依赖的模型包括强大的血管生成因子VEGF及其作为神经调节因子的双重作用。VEGF诱导血管生成的作用主要是通过激活VEGF受体-2 （VEGFR2）同型二聚体介导的，该二聚体可以使用共受体neuropilin 1。Neuropilin 1在调节轴突引导信号中起关键作用，但也可以通过与VEGFR2的关联促进血管生成。VEGF在小鼠中主要以三种亚型VEGF120、VEGF164和VEGF188表达。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。这两种异构体在基质和细胞表面与硫酸肝素蛋白聚糖结合以及与神经磷脂1共受体相互作用的能力上存在差异。只有VEGF164被证明可以结合并激活VEGFR2/neuropilin 1复合物。VEGF164是大脑中的主要亚型。尽管许多研究表明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。本研究假设VEGF通过VEGFR2-neuropilin通路调控发育性神经发生。该假设将在以下几个方面得到验证：1)表征CNS发育性神经发生过程中VEGF、VEGFR2和活化的VEGFR2的细胞类型特异性和表达模式；2)在缺乏VEGF-neuropilin信号传导的小鼠中，测试VEGF-neuropilin信号传导在发育性神经发生中的作用。

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.