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.

项目摘要 中风是世界范围内导致肢体残疾的主要原因，代表着全球社会经济 对人类健康的负担。尽管紧张的研究努力导致了过多的目标和 神经保护剂减少动物卒中所致脑损伤，以神经保护为主 在许多对照临床试验中，这些策略几乎或根本没有效果。这些观察结果 指出，应该有一个范式的转变，以提高翻译效率问题和改善 这种毁灭性的状况。造成翻译障碍的潜在缺失环节包括 在临床前仅依靠脑梗塞面积而不考虑脑肿胀来评估神经保护 学习。此外，在中风的动物模型中缺乏风险因素的包含，而 常见的并发症有血脂异常、高血压、糖尿病和肥胖。 病人的情况。综合证据支持这样的结论，即迫切需要 定义中风病理学，重点是代谢受损条件下的脑肿胀，这是 拟议研究的总体科学前提。我们最近的发现表明，患有 与脑梗塞相比，糖尿病和高脂血症表现出不成比例的脑肿胀 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(VEGFR2)，一个关键的信号分子，血管通透性和 血管生成。因为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是中风患者肥胖增强脑肿胀的基础 阻断VEGFR2的激活可减轻脑肿胀，促进脑功能恢复 肥胖。目的1确定血管内皮生长因子受体2的激活(S)在肥胖患者卒中所致脑肿胀中的作用 通过评估组织学和分子结果来研究小鼠。在目标2中，功能的丧失和获得 研究将评估VEGFR2调节对肥胖增强型卒中诱导的脑的疗效 使用药理学和遗传学方法治疗肿胀。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评价肿胀对卒中长期康复的影响 血管内皮生长因子信号被操纵的小鼠。项目完成后，我们预计将获得 科学证据证实了血管内皮生长因子信号在肥胖增强的脑肿胀中的重要性， 血管内皮生长因子抑制作为肥胖性卒中的治疗策略和减少脑肿胀的应用 促进长期中风康复的方法。这些结果预计将对 通过提供强有力的理由重新调整现有的血管内皮生长因子靶向抗- 治疗中风患者肥胖及其相关并发症的血管生成/抗癌药物。