Identifying compounds that target APOE4 associated brain endothelial dysfunction

鉴定针对 APOE4 相关脑内皮功能障碍的化合物

• 批准号: 10704468
• 负责人: Leon Maing Tai
• 金额: $ 41.22万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-03 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704468
• 关键词: Identifying; compounds; target; APOE4; associated

ABSTRACT APOE genotype is a major genetic risk factor for several neurodegenerative disorders. Compared to APOE3, APOE4 is associated with greater cognitive dysfunction in older adults, increases Alzheimer's disease risk and exacerbates progression of vascular dementia, stroke, and traumatic brain injury. Evidence supports a major role of APOE4 in brain endothelial cell (BEC) dysfunction at the blood-brain barrier in all these conditions. BEC dysfunction can lead to neuronal dysfunction through disrupting the complex neuronal homeostatic environment and via entry of proteins and other toxins that can damage neurons directly and via effects on supporting cells. Due to their unique location, BEC are susceptible to signals from the brain and plasma in neurodegenerative disorders, which may be particularly relevant for inflammation. Indeed, APOE4, neuroinflammation, peripheral inflammation and BEC dysfunction are intimately linked to dementia risk/progression. Our novel in vitro data demonstrate that APOE4-BECs have a unique basal phenotype that results in disruption of their barrier function with inflammatory stimuli, which we have also found in vivo. Based on these data our hypothesis is that APOE4-associated BEC dysfunction is a novel therapeutic target for neurodegenerative disorders. Our goals are to develop our in vitro assays (R61 Phase) and conduct screening and target identification (ID) (R33 phase) to identify novel compounds that mitigate inflammation-induced permeability disruption in APOE4-BECs. Our biological rationale is that APOE4 predisposes BECs to inflammation-induced barrier deficits, thereby increasing the risk/progression of adult-onset neurodegenerative disorders. The novelty lies in our isolation protocols and assays to target inflammation- induced increases in paracellular permeability using APOE4-BECs. The clinical relevance is that APOE4 is a risk factor for neurodegenerative disorders for which there are also in vivo models. Therefore, there are pathways for the transition of positive hits targeting APOE4-associated BEC dysfunction from preclinical to clinical studies.

抽象的 APOE基因型是几种神经退行性疾病的主要遗传危险因素。与apoe3相比 APOE4与老年人的认知功能障碍更大，增加了阿尔茨海默氏病风险和 加剧血管痴呆，中风和脑外伤的进展。证据支持主要 在所有这些条件下，APOE4在血脑屏障中在脑内皮细胞（BEC）功能障碍中的作用。 bec 功能障碍会通过破坏复杂的神经稳态而导致神经元功能障碍 环境以及通过进入蛋白质和其他可以直接损害神经元并通过影响的蛋白质的毒素 支持细胞。由于其独特的位置，BEC容易受到大脑和等离子体信号的影响 神经退行性疾病可能与炎症特别相关。确实，apoe4， 神经炎症，周围炎症和BEC功能障碍与痴呆密切相关 风险/进展。我们的小说体外数据表明，apoe4-becs具有独特的基础表型 导致其在炎症刺激中破坏其屏障功能，我们在体内也发现了它们。基于 在这些数据上，我们的假设是APOE4相关的BEC功能障碍是一个新型的治疗靶点 神经退行性疾病。我们的目标是开发我们的体外测定（R61阶段）并进行筛查 和目标识别（ID）（R33期），以识别减轻炎症诱导的新型化合物 APOE4-BEC中的渗透性破坏。我们的生物学理由是ApoE4易于 炎症引起的屏障缺陷，从而增加成人发作的风险/进展 神经退行性疾病。新颖性在于我们的隔离方案和靶向炎症的测定法 使用APOE4-becs诱导细胞细胞通透性的增加。临床相关性是APOE4是一个 神经退行性疾病的危险因素也有体内模型。因此，有 靶向APOE4相关的BEC功能障碍从临床前到临床前的瞄准正击的途径 临床研究。