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. .

阿尔茨海默病和阿尔茨海默病及相关痴呆（AD/ADRD）是一种新兴的全球健康问题 然而，人们对护理危机的根本机制还没有足够的了解，无法准确地转化。 由于越来越多的证据表明，了解血管对 AD/ADRD 的影响势在必行。 AD 和糖尿病 (DM) 相关的 ADRD 与脑灌注不足有关，67% 的 AD GWAS 基因与 最近的研究表明，可溶性环氧化物水解酶减少。 (sEH) 由于其抗-AD、DM-ADRD 和脑灌注不足动物模型的认知有益 炎症和神经元保护作用，但血管贡献被忽略了。 将花生四烯酸 (AA) 衍生的 EET 和亚油酸 (LA) 衍生的 EpOME 转化为其 分别对应的二醇 DHET 和 DiHOME 的变化，例如 oxylipins 的比例升高。 我们初步发现AD小鼠和ADRD患者体内发现了DHETs/EETs和DiHOMEs/EpOMEs。 基因（CYP2J2、2C8、2C9）中的 SNP 编码催化 AA 和 LA 生成 EET 和 EpOME 的酶， 我们还发现，编码 sEH 的 EPHX2 与 ARIC-NCS 中的 AD 相关。 抑制剂 (sEHi) TPPU 可逆转认知障碍、肌源性反应 (MR) 受损和自我调节 DM-ADRD 和 AD 大鼠的脑血流量 (CBF) 和神经血管单元 (NVU) 功能障碍。 AD/ADRD大鼠表现出脑灌注不足、血脑屏障（BBB）渗漏增强、神经变性、 据报道，大脑 Kir2.1 活性降低与脑毛细血管中 PIP2 水平降低相关 由于 PLA2 活性增强，该提案将检验抑制 sEH 的假设。 协同调节 PLA2-AA-EETs-DHETS 和 PLA2-LA-EpOMEs-DiHOMEs 途径以逆转 通过改善 CBF 自动调节、维持 BBB 和 我们将比较血管功能（MR、CBF 自动调节和功能性充血）、AD TPPU 治疗的两性 DM 患者的表型、PLA2、sEH、PlP2、Kir2.1 和 oxylipins 的区域脑水平 我们还将比较 ADRD 和 AD 大鼠对 EET/DHET 异构体混合物的血管反应，以及 脑动脉和小动脉中的 EpOMEs/DiHOMEs，以及对钾和钾升高的血管舒张反应 从对照、AD 和 ADRD 大鼠的两性中分离出小动脉-毛细血管中的氧脂素异构体混合物 进一步探索受 sEH 抑制影响的具体途径 该项目将解决关键问题。 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 催化活性的生物学结果应为该提案奠定基础。 针对这些途径的新药的发现可以逆转脑血管功能障碍，从而预防 发生并减缓 AD/ADRD 的进展。 。