VEGF in Neurprotection and Neurogenesis

描述(申请人提供)：血管内皮生长因子(VEGF或VEGF-A)是一种低氧诱导的分泌型蛋白，与内皮细胞上的受体酪氨酸激酶相互作用，促进血管生成。最近的证据表明，血管内皮生长因子还可能直接作用于神经元，产生神经营养和神经保护作用，并作用于成年大脑中的神经元前体细胞，以刺激神经发生--前体细胞通过这一过程分化为成熟的神经元表型。这项工作广泛的总体目标是了解血管内皮生长因子如何影响神经元及其细胞前体，并确定血管内皮生长因子在中风和其他神经疾病中可能的治疗作用。这一提议背后的假设是，血管内皮生长因子直接作用于(A)大脑神经元，以保护它们免受缺氧、缺血和相关损伤，以及(B)神经元前体促进神经发生。其具体目的是：(1)明确血管内皮生长因子在体外保护大脑皮层神经元免受模拟缺血和相关损伤的受体和信号转导途径；(2)研究血管内皮生长因子在体内对局灶性脑缺血神经元的保护机制；(3)确定血管内皮生长因子刺激体外培养的大脑皮层神经发生的机制；(4)确定血管内皮生长因子在体内促进神经发生的作用，涉及哪些神经增殖区，哪些血管内皮生长因子受体参与，这种作用是通过刺激细胞分裂还是抑制细胞死亡产生的，以及靶细胞的迁移和功能命运。

DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF or VEGF-A) is a hypoxia-inducible secreted protein that interacts with receptor tyrosine kinases on endothelial cells to promote angiogenesis. Recent evidence indicates that VEGF may also act directly on neurons to produce neurotrophic and neuroprotective effects, and on neuronal precursor cells in the adult brain to stimulate neurogenesis -- the process through which precursor cells differentiate towards a mature neuronal phenotype. The broad, overall objective of this work is to understand how VEGF affects neurons and their cellular precursors, and to identify possible therapeutic roles for VEGF in stroke and other neurological disorders. The hypothesis underlying this proposal is that VEGF acts directly on (A) cerebral neurons to protect them from hypoxia, ischemia and related insults and (B) neuronal precursors to promote neurogenesis. The Specific Aims are to: (1) define the receptors and signal-transduction pathways through which VEGF protects cortical neurons from simulated ischemia and related insults in vitro, (2) investigate the mechanism by which VEGF protects neurons from focal cerebral ischemia in vivo, (3) determine the mechanism by which VEGF stimulates neurogenesis in cerebral cortical cultures in vitro, and (4) characterize the neurogenesis-promoting effect of VEGF in vivo with respect to which neuroproliferative zones are affected, which VEGF receptors are involved, whether the effect is produced by stimulating cell division or inhibiting cell death, and the migratory and functional fates of the target cells.