VEGF in Ischemic Neuroprotection, Neurodegeneration and Repair

VEGF 在缺血性神经保护、神经变性和修复中的作用

• 批准号: 8319421
• 负责人: David Alan Greenberg
• 金额: $ 41.59万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319421
• 关键词: Acute; Address; Adult; Angiogenic Factor; Attenuated; Biological Assay; Brain; Brain Ischemia; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; Caspase; Cell Culture Techniques; Cell Death; Cell Proliferation; Cell Survival; Cells; Cerebral Ischemia; Cerebral cortex; Cerebrum; Cessation of life; Chemotaxis; Coculture Techniques; Contralateral; DLG4 gene; DNA Damage; Electrophysiology (science); Endothelial Cells; Endothelium; Event; Exclusion; Family; Family member; Glucose; Goals; Grant; Growth Factor; Hypoxia; Immunohistochemistry; In Vitro; Infarction; Injury; Ischemia; Lead; Measures; Mediating; Mediator of activation protein; Middle Cerebral Artery Occlusion; Mitochondria; Mus; Nerve; Nerve Degeneration; Nervous system structure; Neurites; Neurologic; Neuronal Differentiation; Neurons; Outcome; Oxygen; Pathway interactions; Patients; Phase; Placental Growth Factor; Process; Production; Protein Kinase; Proteins; Rattus; Recovery; Research; Severities; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Specificity; Stroke; Subfamily lentivirinae; Synaptophysin; Testing; Time; Trypan Blue; VEGFA gene; VEGFC gene; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular System; Western Blotting; Work; adult neurogenesis; base; cell injury; cell motility; deprivation; disability; functional outcomes; improved; in vivo; inhibitor/antagonist; migration; neurobehavioral; neurogenesis; neuroprotection; novel therapeutic intervention; patch clamp; pigment epithelium-derived factor; precursor cell; prevent; public health relevance; receptor; repaired; subventricular zone; synaptogenesis; therapeutic target

DESCRIPTION (provided by applicant): Stroke is a major cause of neurological disability and death, but most patients improve over weeks to months after stroke, suggesting that endogenous mechanisms exist for limiting and reversing the effects of brain ischemia. These include neuroprotection, which prevents the progression of reversible to irreversible injury, and neuroregeneration, which replaces lost cells, circuits and functions. In previous work supported by this grant, we found that vascular endothelial growth factor (VEGF, or VEGFA) protects neurons from hypoxia in vitro and ischemia in vivo, promotes adult neurogenesis, improves histological and functional outcome after experimental stroke, and stimulates neurite outgrowth. These effects are mediated largely through the VEGFR2 receptor, although we have also found that VEGFB, which acts via VEGFR1, has some of the same actions. Other endogenous VEGF family members-VEGFC, VEGFD, and placental growth factor (PlGF)- have different receptor specificities, and little is known about their effects on the nervous system. We propose to continue our study of VEGF effects on neuroprotection, neurogenesis and recovery after stroke, based on the hypothesis that different VEGF family members operate via distinct but overlapping signaling pathways to regulate diverse aspects of ischemic neuroprotection, ischemia-induced neurogenesis, and post-ischemic recovery. This hypothesis will be tested by addressing the following specific aims: (1) Compare the neuroprotective and neurogenesis-promoting effects of VEGFB and VEGFC; (2) Evaluate the ability of VEGFB and VEGFC to enhance repair and recovery in the post-acute phase following experimental stroke; (3) Identify the signal transduction pathways employed in the neuroprotective and neurogenesis-promoting effects of VEGFB and VEGFC; and (4) Determine the contribution of endothelial cells to the neuroprotective and neurogenesis-promoting effects of VEGFB and VEGFC. PUBLIC HEALTH RELEVANCE: In previous work supported by this grant, we found that vascular endothelial growth factor (VEGF, or VEGFA) protects neurons from oxygen deprivation and brain ischemia, promotes the production of new neurons (neurogenesis), improves outcome after experimental stroke, and stimulates outgrowth of nerve processes (neurites). We propose to continue our study of VEGF effects on neuroprotection, neurogenesis and recovery after stroke, based on the hypothesis that different VEGF family members (VEGFB and VEGFC) operate via distinct but overlapping signaling pathways to regulate ischemic neuroprotection, ischemia-induced neurogenesis, and post-ischemic recovery. The proposed studies will help to delineate the potential and limitations of VEGF family members in the treatment of stroke.

描述（由申请人提供）：卒中是神经功能障碍和死亡的主要原因，但大多数患者在卒中后数周至数月内改善，表明存在限制和逆转脑缺血效应的内源性机制。这些包括神经保护，防止可逆损伤发展为不可逆损伤，以及神经再生，取代失去的细胞，电路和功能。在以前的研究中，我们发现血管内皮生长因子（VEGF或VEGFA）在体外保护神经元免受缺氧和体内缺血，促进成人神经发生，改善实验性中风后的组织学和功能结果，并刺激神经突生长。这些作用主要通过VEGFR 2受体介导，尽管我们也发现通过VEGFR 1起作用的VEGFB具有一些相同的作用。其他内源性VEGF家族成员-VEGFC、VEGFD和胎盘生长因子（PlGF）-具有不同的受体特异性，并且关于它们对神经系统的作用知之甚少。我们建议继续研究VEGF对脑卒中后神经保护、神经发生和恢复的作用，这是基于以下假设：不同的VEGF家族成员通过不同但重叠的信号通路来调节缺血性神经保护、缺血诱导的神经发生和缺血后恢复的各个方面。本研究将通过以下具体目的来验证这一假设：（1）比较VEGFB和VEGFC的神经保护和神经发生促进作用;（2）评价VEGFB和VEGFC在实验性卒中后急性期增强修复和恢复的能力;（3）鉴定VEGFB和VEGFC的神经保护和神经发生促进作用中所采用的信号转导通路;（4）确定内皮细胞在VEGFB和VEGFC的神经保护和促进神经发生作用中的作用。 公共卫生相关性：在这项资助支持的先前工作中，我们发现血管内皮生长因子（VEGF或VEGFA）保护神经元免受缺氧和脑缺血，促进新神经元（神经发生）的产生，改善实验性中风后的结果，并刺激神经突起（神经突）的生长。我们建议继续研究VEGF对脑卒中后神经保护、神经发生和恢复的作用，这是基于不同的VEGF家族成员（VEGFB和VEGFC）通过不同但重叠的信号通路来调节缺血性神经保护、缺血诱导的神经发生和缺血后恢复的假设。拟议的研究将有助于阐明VEGF家族成员在卒中治疗中的潜力和局限性。