GROWTH FACTORS INFLUENCE STROKE RECOVERY

生长因素影响中风康复

• 批准号: 6112048
• 负责人: SETH FINKLESTEIN
• 金额: $ 23.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112048
• 关键词: antisense nucleic acid; biomarker; bone morphogenetic proteins; brain; cardiovascular disorder chemotherapy; cerebral ischemia /hypoxia; disease /disorder model; drug administration rate /duration; fibroblast growth factor; growth factor receptors; immunocytochemistry; in situ hybridization; laboratory rat; nervous system regeneration; neuroprotectants; nitric oxide synthase; northern blottings; recombinant proteins; stroke; synaptogenesis; western blottings

Focal stroke, i.e., the death of a region of brain tissue due to occlusion of a cerebral artery, remains a major public health problem in the U.S. and around the world. Stroke may cause deficits of motor, cognitive, language, or visual function. Although often incomplete, some degree of functional and structural reorganization of the remaining intact brain. In previous studies, we have investigate the role of polypeptide growth factors as molecular signals initiating the cascade of molecular and cellular events underlying recovery after stroke. In particular, we found that the exogenous administration of recombinant basic fibroblast growth factor (bFGF) or osteogenic protein-1 (OP-1, BMP-7) enhanced functional recovery in rodent models of focal stroke, even when given long after stroke had occurred. This effect was not due to reduction in infract volume, but presumably to enhancement of new neuronal sprouting and synapse formation in the intact uninjured brain. In the proposed studies, we will: (1) investigate the dose and time window characteristics of exogenous bFGF and OP-1 treatment in enhancing functional recovery, (2) examine the effects of the blockade of endogenous bFGF and OP-1 in inhibiting recovery, and (3) explore the molecular and cellular mechanisms of enhancement of functional recovery by bFGF and OP-1, including studies of the expression of molecular markers of new axonal and dendritic sprouting and synapse formation, and morphological studies. These studies are expected to lead to new understanding of the molecular mechanisms of recovery after stroke, and may lead to the development of polypeptide growth factors as a new molecular treatment to enhance stroke recovery.

局灶性中风，即由于脑动脉闭塞而导致脑组织区域死亡，仍然是美国和世界各地的一个主要公共卫生问题。中风可能导致运动、认知、语言或视觉功能缺陷。尽管通常是不完整的，但剩余的完整大脑进行了一定程度的功能和结构重组。在之前的研究中，我们研究了多肽生长因子作为分子信号启动中风后恢复的分子和细胞事件级联的作用。特别是，我们发现外源性给予重组碱性成纤维细胞生长因子（bFGF）或成骨蛋白-1（OP-1、BMP-7）可增强局灶性中风啮齿动物模型的功能恢复，即使是在中风发生后很长时间内给予。这种效果并不是由于梗塞体积的减少，而是由于完整的未受伤大脑中新神经元萌芽和突触形成的增强。在拟议的研究中，我们将：（1）研究外源性bFGF和OP-1治疗促进功能恢复的剂量和时间窗特征，（2）检查内源性bFGF和OP-1的阻断在抑制恢复中的作用，以及（3）探索bFGF和OP-1促进功能恢复的分子和细胞机制，包括新轴突和神经元分子标志物表达的研究。 树突发芽和突触形成以及形态学研究。这些研究有望带来对中风后恢复的分子机制的新认识，并可能导致多肽生长因子的发展，作为一种新的分子治疗方法来促进中风恢复。