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

针对肥胖受试者中风引起的脑肿胀：VEGF 的作用

• 批准号: 9523808
• 负责人: Sunghee Cho
• 金额: $ 40.47万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9523808
• 关键词: Acute; Address; Age; Animal Model; Animals; Antineoplastic Agents; Awareness; Brain Edema; Brain Injuries; CD36 gene; Clinical; Clinical Trials; Comorbidity; Complication; Controlled Clinical Trials; Data; Development; Diabetes Mellitus; Dyslipidemias; Effectiveness; Genetic Polymorphism; Goals; Gold; Health; Histologic; Human; Hyperlipidemia; Hypertension; Impairment; Infarction; Intervention; Ischemic Stroke; KDR gene; Lead; Life; Link; Metabolic; Metabolic Diseases; Mission; Molecular; Morbidity - disease rate; Motor; Mus; Neuroprotective Agents; Obese Mice; Obesity; Outcome; Pathology; Pathway interactions; Patients; Permeability; Pharmacology; Phase; Physically Handicapped; Play; Recovery; Recovery of Function; Research; Risk Factors; Role; Signal Transduction; Signaling Molecule; Stroke; Swelling; Translating; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vegf inhibition; angiogenesis; base; cognitive function; density; disability; efficacy study; expectation; gain of function; genetic approach; human model; improved; inhibitor/antagonist; loss of function; mortality; neuroprotection; novel; novel therapeutics; post stroke; pre-clinical; preclinical efficacy; preclinical study; socioeconomics; stroke incidence; stroke model; stroke outcome; stroke patient; stroke recovery; stroke therapy; stroke treatment; success; therapeutic target; treatment strategy

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.

项目概要 中风是全球身体残疾的主要原因，代表着全球社会经济问题 给人类健康造成负担。尽管大量的研究工作导致了过多的目标和 神经保护剂可减少中风引起的动物脑损伤，基于神经保护的 在许多对照临床试验中，策略的效果很小或没有效果。这些观察 表明应该进行范式转变，以增强转化效率问题并改善 这种毁灭性的情况。造成翻译障碍的潜在缺失环节包括 仅依靠梗死面积而不考虑脑肿胀来衡量临床前的神经保护作用 研究。此外，中风动物模型中很少包含危险因素，而 经常观察到血脂异常、高血压、糖尿病和肥胖等合并症 患者的情况。综合证据支持以下结论：迫切需要 定义中风病理学，重点关注代谢受损条件下的脑肿胀，即 拟议研究的总体科学前提。我们最近的研究结果表明，患有 与梗塞相比，糖尿病和高脂血症表现出不成比例的更大脑肿胀 体积，并且脑肿胀的增强与血管水平的增加密切相关 内皮生长因子受体 2 (VEGFR2)，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 VEGFR2 是肥胖导致中风时脑肿胀的基础 阻断 VEGFR2 激活可减少肿胀并促进功能恢复 肥胖。目标 1 将确定 VEGFR2 激活对肥胖患者中风引起的脑肿胀的作用 通过评估组织学和分子结果来评估小鼠。在目标 2 中，功能的损失和获得 研究将评估 VEGFR2 调节对肥胖加剧的中风诱发大脑的功效 使用药理学和遗传学方法进行肿胀。目标 3 将确定大脑的影响 通过评估肥胖者的长期运动和认知功能来评估肿胀对长期中风恢复的影响 VEGF 信号传导受到操纵的小鼠。项目完成后，我们期望获得 科学证据证实 VEGF 信号传导在肥胖加剧的脑肿胀中的重要性， VEGF 抑制作为肥胖中风的治疗策略的效用，并减少脑肿胀 促进长期中风康复的方法。这些结果预计将产生重大影响 通过为现有的 VEGF 靶向抗药物的重新利用提供强有力的理由来产生影响 血管生成/抗癌药物用于治疗患有肥胖症及其相关合并症的中风患者。