Vascular mechanisms of inhibition of sEH as a novel therapy for AD/ADRD

抑制 sEH 作为 AD/ADRD 新疗法的血管机制

• 批准号: 10525694
• 负责人: Fan Fan
• 金额: $ 172.04万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525694
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; Animal Model; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Atlases; Biology; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; CYP2J2 gene; Capillary Endothelial Cell; Cell membrane; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Chronic; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Diabetes Mellitus; Dietary Fats; Disease; Endothelium; Enzymes; Epoxide hydrolase; Exhibits; Extravasation; Female; Foundations; Functional disorder; Genes; Genetic; Glycols; Healthcare; Hippocampus (Brain); Homeostasis; Human; Hyperemia; Impaired cognition; Impairment; In Vitro; Inflammation; Isomerism; Knowledge; Link; Linoleic Acids; Lung; Mus; Mutation; Nerve Degeneration; Neurons; Pathway interactions; Patients; Perfusion; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phospholipase A2; Play; Potassium; Rattus; Regulation; Reporting; Role; Testing; Tissues; Translating; Translations; Vascular Permeabilities; Vasodilation; arteriole; base; blood-brain barrier permeabilization; cerebral artery; cerebral capillary; cerebral hypoperfusion; cerebrovascular; cognitive disability; cognitive enhancement; cognitive function; diabetic; genome wide association study; global health; hypoperfusion; improved; inhibitor; linoleates; male; middle cerebral artery; neglect; neurovascular unit; new therapeutic target; novel therapeutics; parenchymal arterioles; precision medicine; prevent; protective effect; response; sex; treatment trial; vascular contributions

Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD) is an emerging global health care crisis. However, underlying mechanisms have not been understood well enough for translation to precision medicine. Understanding vascular contribution to AD/ADRD is imperative since increasing evidence suggests AD and diabetic (DM)-related ADRD are associated with brain hypoperfusion, and 67% of AD GWAS genes are expressed in the cerebral vasculature. Recent studies demonstrated that reduction of soluble epoxide hydrolase (sEH) is beneficial to cognition in AD, DM-ADRD, and cerebral hypoperfusion animal models due to its anti- inflammatory and neuronal protective effects, but vascular contribution has been neglected. sEH is an enzyme that transforms arachidonic acid (AA)-derived EETs and linoleic acid (LA)-derived EpOMEs to their corresponding diols DHETs and DiHOMEs, respectively. Changes in oxylipins, such as the elevated ratio of DHETs/EETs and DiHOMEs/EpOMEs, were found in AD mice and ADRD patients. We preliminary found that SNPs in genes (CYP2J2, 2C8, 2C9) encoding enzymes that catalyze AA and LA to EETs and EpOMEs, and EPHX2 encoding sEH are linked with AD in the ARIC-NCS. We also found that a highly selective sEH inhibitor (sEHi) TPPU reversed cognitive disability, impaired myogenic response (MR) and autoregulation of cerebral blood flow (CBF), and neurovascular unit (NVU) dysfunction in DM-ADRD and AD rats. Moreover, AD/ADRD rats displayed brain hypoperfusion, enhanced blood-brain barrier (BBB) leakage, neurodegeneration, and reduced brain Kir2.1 activity that has been reported to associate with reduced PIP2 levels in cerebral capillary endothelial cells due to enhanced PLA2 activity. This proposal will test the HYPOTHESIS that inhibition of sEH synergistically modulates the PLA2-AA-EETs-DHETS and PLA2-LA-EpOMEs-DiHOMEs pathways to reverse cognitive impairments and enhance brain perfusion by ameliorating CBF autoregulation, maintaining BBB and NVU function. We will compare vascular function (MR, CBF autoregulation, and functional hyperemia), AD phenotypes, regional brain levels of PLA2, sEH, PlP2, Kir2.1, and oxylipins in TPPU-treated both sexes of DM- ADRD and AD rats. We will also compare vascular responses to isomer mixtures of EETs/DHETs, and EpOMEs/DiHOMEs in cerebral arteries and arterioles, and vasodilation responses to elevated potassium and isomer mixtures of oxylipins in arterioles-capillaries isolated from both sexes of control, AD, and ADRD rats to further explore the specific pathways that are affected by inhibition of sEH. This project will address critical knowledge gaps of the vascular contribution of sEHi on cognitive protection and the “next steps” in explaining the biology of the catalytic activity of the sEH. Results generated from this proposal should lay the foundation for the discovery of new drugs targeting these pathways to reverse cerebral vascular dysfunction to prevent the onset and slow the progression of AD/ADRD. .

阿尔茨海默氏病和阿尔茨海默氏病和相关痴呆症（AD/ADRD）是一种新兴的全球健康 护理危机。但是，潜在的机制尚未足够理解，无法翻译至精确 药品。了解对AD/ADRD的血管贡献是必须的，因为越来越多的证据表明 AD和糖尿病（DM）相关的ADRD与脑部灌注不足有关，而67％的AD GWAS基因为 在大脑脉管系统中表达。最近的研究表明，固体环氧水解酶的减少 （SEH）由于其抗 - 炎症和神经元受保护的作用，但血管贡献已被忽略。 SEH是一种酶 这将蛛网膜酸（AA）衍生的Eets和亚油酸（LA）衍生的EPOMES转化为它们 相应的DIOLS DHET和DIHOMES。黄磷脂的变化，例如升高的比率 在AD小鼠和ADRD患者中发现了DHET/EET和DIHOMES/EPOMES。我们的初步发现 该基因（CYP2J2、2C8、2C9）中的SNP编码催化AA和LA的酶，促成Eets and Epomes， 编码SEH的EPHX2与ARIC-NC中的AD相关。我们还发现高度选择性的SEH 抑制剂（SEHI）TPPU逆转了认知障碍，肌原源性反应受损（MR）和自动调节 DM-ADRD和AD大鼠中的脑血流（CBF）和神经血管单元（NVU）功能障碍。而且， AD/ADRD大鼠表现出脑部灌注不足，增强的血脑屏障（BBB）泄漏，神经变性， 并降低了脑KIR2.1活性，据报道与脑毛细管中的PIP2水平降低相关 由于PLA2活性增强而引起的内皮细胞。该提议将检验抑制SEH的假设 协同调节PLA2-AA-EETS-DHET和PLA2-LA-EPOMES-DIHOMES途径以逆转 认知障碍并通过改善CBF自动调节，保持BBB和 NVU功能。我们将比较血管功能（MR，CBF自动调节和功能性充血），AD 在TPPU处理的两性中，表型，PLA2，SEH，PLP2，KIR2.1和oxylipins的区域大脑水平 ADRD和AD大鼠。我们还将比较Eet/DHET的异构体混合物的血管反应，以及 脑动脉和小动脉中的表现/二核酸群，以及对钾升高和 从对照，AD和ADRD大鼠分离到的小动脉毛细血管中的阿氧蛋白的异构体混合物 进一步探索受SEH抑制影响的特定途径。该项目将解决关键 SEHI对认知保护的血管贡献的知识差距以及解释的“下一步” SEH催化活性的生物学。该提案产生的结果应为 发现针对这些途径以逆转脑血管功能障碍的新药，以防止 发作并减慢AD/ADRD的进展。 。