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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

基本信息

批准号：
10355739
负责人：
Leon Maing Tai
金额：
$ 35.89万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-03 至 2023-08-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355739
关键词：
Address Adult Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Apolipoprotein E Behavioral Benchmarking Biological Biological Assay Blood - brain barrier anatomy Brain Cell Separation Cell physiology Cells Characteristics Classification Clinical Clinical Research Cognitive deficits Complex Data Disease Dose Elderly Electrical Resistance Endothelium Environment Evaluation Functional disorder Genotype Goals Impaired cognition In Vitro Inferior Inflammation Inflammation Process Inflammatory Lead Libraries Link Lipopolysaccharides Location Longevity Measures Mind Modeling Mus Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Pathway interactions Peripheral Permeability Phase Phenotype Plasma Proteins Protocols documentation Public Health Risk Risk Factors Role Safety Signal Transduction Standardization Stimulus Stroke Supporting Cell Testing Toxic effect Toxin Traumatic Brain Injury Vascular Dementia assay development base brain endothelial cell clinical application clinically relevant dementia risk endothelial dysfunction experimental study genetic risk factor in vitro Assay in vitro Model in vivo in vivo Model neuroinflammation new therapeutic target novel pre-clinical protein protein interaction repaired response screening therapeutic target

项目摘要

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 基因型是多种神经退行性疾病的主要遗传危险因素。与APOE3相比， APOE4 与老年人更大的认知功能障碍有关，增加阿尔茨海默病的风险，加剧血管性痴呆、中风和创伤性脑损伤的进展。证据支持主要 APOE4 在所有这些条件下血脑屏障的脑内皮细胞 (BEC) 功能障碍中的作用。商务英语委员会功能障碍可通过破坏复杂的神经元稳态而导致神经元功能障碍环境以及通过蛋白质和其他毒素的进入可以直接损害神经元并通过影响支持细胞。由于其独特的位置，BEC 很容易受到来自大脑和血浆的信号的影响。神经退行性疾病，这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。我们的新体外数据表明 APOE4-BEC 具有独特的基础表型炎症刺激会导致其屏障功能遭到破坏，我们在体内也发现了这一点。基于根据这些数据，我们的假设是 APOE4 相关的 BEC 功能障碍是一种新的治疗靶点神经退行性疾病。我们的目标是开发体外测定（R61 阶段）并进行筛选和目标识别 (ID)（R33 阶段），以确定减轻炎症诱导的新型化合物 APOE4-BEC 的渗透性破坏。我们的生物学原理是 APOE4 使 BEC 易于炎症引起的屏障缺陷，从而增加成人发病的风险/进展神经退行性疾病。新颖之处在于我们针对炎症的分离方案和检测—— 使用 APOE4-BEC 诱导细胞旁通透性增加。临床相关性是 APOE4 是神经退行性疾病的危险因素，也有体内模型。因此，有针对 APOE4 相关 BEC 功能障碍的阳性命中从临床前到临床前的转变途径临床研究。