Targeting stroke-induced brain swelling in obese subjects: role of VEGF

项目摘要 中风是全球身体残疾的主要原因， 对人类健康的负担。尽管密集的研究工作，导致了过多的目标， 神经保护剂，以减少中风引起的脑损伤的动物，神经保护为基础的 在许多对照临床试验中，这些策略几乎没有或没有效果。这些观察结果 指出，应该有一个范式的转变，以提高翻译效率的问题，并改善 这种毁灭性的状况。可能导致翻译障碍的缺失环节包括 仅仅依靠梗死面积而不考虑脑肿胀来评估临床前神经保护作用 问题研究此外，在中风的动物模型中包含的危险因素很少，而 经常观察到血脂异常、高血压、糖尿病和肥胖等合并症 患者的条件。综合证据支持以下结论：迫切需要 定义中风病理学，重点是代谢受损条件下的脑肿胀， 为拟议的研究提供总体科学前提。我们最近的发现表明， 糖尿病和高脂血症患者与梗死患者相比， 体积，脑肿胀增强与血管水平增加密切相关 内皮生长因子受体2（VEGFR 2），血管通透性的关键信号分子， 血管生成由于肥胖是导致包括糖尿病在内的代谢紊乱的诱因 和血脂异常，我们假设VEGFR 2是肥胖增强脑肿胀的基础， 阻断VEGFR 2的激活可以减少肿胀并促进功能恢复， 肥胖目的1将确定VEGFR 2激活在肥胖患者中风诱导的脑肿胀中的作用。 小鼠通过评估组织学和分子结果。在目标2中，函数的损失和增益 研究将评估VEGFR 2调节对肥胖增强的中风诱导的大脑的功效， 肿胀使用药理学和遗传学方法。目标3将确定大脑的影响 通过评估肥胖患者的长期运动和认知功能， 其中VEGF信号传导被操纵的小鼠。在项目完成后，我们预计将获得 建立VEGF信号在肥胖增强的脑肿胀中的重要性的科学证据， VEGF抑制作为肥胖中风的治疗策略的效用，以及减少脑肿胀作为 一种促进中风长期康复的方法预计这些结果将产生重大影响。 通过为重新利用可用的VEGF靶向抗- 血管生成/抗癌药物，以治疗患有肥胖症及其相关合并症的中风患者。

Project Summary Stroke is the leading cause of physical disability worldwide and represents a global socioeconomic burden to human health. Despite an intense research effort that led to a plethora of targets and neuroprotectants to reduce stroke-induced brain injury in animals, the neuroprotection-based strategies resulted in little or no efficacy in numerous controlled clinical trials. These observations indicate that there should be a paradigm shift to enhance the translational efficacy issue and improve this devastating condition. Potential missing links that account for the translational hindrances include solely relying on infarct size without considering brain swelling to gauge neuroprotection in preclinical studies. In addition, there is a paucity of inclusion of risk factors in animal models of stroke, whereas comorbidities such as dyslipidemia, hypertension, diabetes, and obesity are frequently observed conditions in patients. The combined evidence supports the conclusion that there is a critical need to define stroke pathology focusing on brain swelling in metabolically compromised conditions, which is the overall scientific premise for the proposed research. Our recent findings showed that mice with diabetes and hyperlipidemia displayed disproportionately larger brain swelling compared to infarct volume, and the enhanced brain swelling was closely associated with an increased level of vascular endothelial growth factor receptor 2 (VEGFR2), a key signaling molecule for vascular permeability and angiogenesis. As obesity is a precipitating cause leading to metabolic disorders including diabetes and dyslipidemia, we hypothesized that VEGFR2 underlies obesity-enhanced brain swelling in stroke and that blocking VEGFR2 activation reduces the swelling and promotes functional recovery in obesity. Aim 1 will identify the role of VEGFR2 activation(s) on stroke-induced brain swelling in obese mice by assessing histological and molecular outcomes. In Aim 2, the loss and gain of function studies will evaluate the efficacy of VEGFR2 modulation on obesity-enhanced stroke-induced brain swelling using pharmacological and genetic approaches. Aim 3 will determine the impact of brain swelling on long-term stroke recovery by assessing long-term motor and cognitive function in obese mice where VEGF signaling is manipulated. At the completion of the project, we expect to obtain scientific evidence establishing the importance of VEGF signaling in obesity-enhanced brain swelling, the utility of VEGF inhibition as a treatment strategy in obesity stroke, and reducing brain swelling as an approach to promoting long-term stroke recovery. These results are expected to have a significant impact by providing strong justification for the repurposing of available VEGF-targeted anti- angiogenic/anti-cancer drugs to treat stroke patients with obesity and its associated comorbidities.