Role of GPR39 in Aging-Related Vascular Cognitive Impairment (VCI)

GPR39 在衰老相关血管认知障碍 (VCI) 中的作用

• 批准号: 10538329
• 负责人: Nabil J Alkayed
• 金额: $ 197.82万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538329
• 关键词: Acute; Affect; Age; Age-Months; Age-associated memory impairment; Aging; Agonist; Alzheimer' s Disease; Animal Model; Autopsy; Biological Availability; Blood Vessels; Blood capillaries; Blood flow; Brain; CSPG4 gene; Cerebral small vessel disease; Cerebrum; Chronic; Cognitive aging; Cognitive deficits; Data; Dementia; Disease; DsRed; Endothelial Cells; Endothelium; Epoxide hydrolase; Exhibits; Female; Functional disorder; GPR39 gene; GTP-Binding Protein alpha Subunits, Gs; Human; Hydrolase; Image; Impaired cognition; Impairment; Ischemia; Knockout Mice; Legal patent; Link; Lipids; Magnetic Resonance Imaging; Measures; Memory Loss; Memory impairment; Metabolic; Microcirculation; Microvascular Dysfunction; Molecular Target; Mus; Neurons; Optical Coherence Tomography; Patients; Perfusion; Pericytes; Pharmaceutical Preparations; Pharmacology; Play; Property; Reporter; Role; Sex Differences; Signal Transduction; Signaling Molecule; Single Nucleotide Polymorphism; Testing; Therapeutic; Transgenic Animals; Transgenic Mice; Up-Regulation; Vascular Cognitive Impairment; Vascular Dementia; Vascular Diseases; Vasodilator Agents; Vibrissae; White Matter Hyperintensity; Zinc supplementation; age related; aged; aging population; arteriole; brain tissue; cerebral hypoperfusion; cerebrovascular; endothelial dysfunction; enzyme activity; improved; in vivo; innovation; lipidomics; male; new therapeutic target; novel; novel therapeutics; phosphoproteomics; post stroke; preservation; prevent; promoter; receptor; response; spatial memory; treatment effect; two photon microscopy

Summary Abstract Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease. The most common cause of VCI is cerebral small vessel disease (SVD). The mechanisms underlying SVD are poorly understood, with no specific treatments currently available to prevent or treat SVD and associated VCI. We have previously found increased expression and activity of the enzyme soluble epoxide hydrolase (sEH) in microvascular endothelium of human brain tissue from deceased patients with pre-mortem dementia and postmortem histopathological evidence of SVD. Transgenic mice expressing the human sEH gene under the endothelial Tie2 promoter (Tie2-hsEH) exhibit age-dependent cognitive deficit, supporting a causal link between endothelial sEH upregulation and cognitive impairment. sEH is responsible for the breakdown of 14,15- epoxyeicosatrienoate (14,15-EET), an endogenous lipid signaling molecule with vasodilator and vasoprotective properties that preferentially acts on small blood vessels. We recently identified G protein-coupled receptor 39 (GPR39) as a molecular target for 14,15-EET localized in human and mouse brains in peri-capillary pericytes. The current proposal will test the hypothesis that endothelial-pericyte EET/GPR39 signaling plays a protective role against aging- and SVD-related cognitive impairment by preserving capillary blood flow. In support of this hypothesis, our preliminary data shows that GPR39 knockout mice (GPR39KO) exhibit spatial memory deficit, and GPR39 SNPs in humans correlate with white matter hyperintensity volume, an MRI marker of VCI. In Aim 1, we will use male and female WT and GPR39 KO mice at 3, 12 and 18 months of age to test the hypothesis that GPR39 is upregulated in pericytes to compensate for loss of endothelial EETs in order to maintain adequate capillary flow and mitigate age-related cognitive decline. We will use unbiased, high-throughput lipidomics to characterize age-dependent changes in brain oxylipins, and phosphoproteomics to investigate changes in downstream signaling in isolated pericytes. Aim 2 will determine the role of GPR39 in cognitive impairment related to chronic cerebral hypoperfusion (CCH). We will determine if GPR39 deletion exacerbates CCH-related capillary dysfunction and cognitive impairment, which can be reversed by increasing endothelial EETs in WT, but not GPR39 KO mice. Aim 3 will determine if a GPR39 agonist can protect against cognitive impairment and capillary dysfunction in aged mice and mice with CCH. The proposed studies are highly significant and technically and conceptually innovative, as they will advance understanding of mechanisms underlying VCI, and propose a potential novel therapy for aging-related VCI.

摘要 摘要 血管性认知障碍（VCI）是继阿尔茨海默氏病之后导致痴呆的第二常见原因。 VCI 最常见的原因是脑小血管疾病 (SVD)。 SVD 的基本机制是 人们对此知之甚少，目前尚无可用于预防或治疗 SVD 及相关 VCI 的特异性治疗方法。 我们之前发现可溶性环氧化物水解酶（sEH）的表达和活性增加 死前痴呆症患者脑组织的微血管内皮细胞 SVD 的死后组织病理学证据。表达人类sEH基因的转基因小鼠 内皮Tie2启动子（Tie2-hsEH）表现出年龄依赖性认知缺陷，支持之间的因果关系 内皮 sEH 上调和认知障碍。 sEH 负责 14,15- 环氧二十碳三烯酸酯 (14,15-EET)，一种具有血管扩张和血管保护作用的内源性脂质信号分子 优先作用于小血管的特性。我们最近发现了 G 蛋白偶联受体 39 (GPR39) 作为 14,15-EET 的分子靶标，定位于人和小鼠大脑毛细血管周细胞中。 目前的提案将检验内皮-周细胞 EET/GPR39 信号传导发挥保护作用的假设。 通过保护毛细血管血流量来对抗衰老和 SVD 相关的认知障碍。为了支持这一点 假设，我们的初步数据显示 GPR39 敲除小鼠（GPR39KO）表现出空间记忆缺陷， 人类中的 GPR39 SNP 与白质高信号体积（VCI 的 MRI 标记）相关。瞄准 1、我们将使用3、12和18月龄的雄性和雌性WT和GPR39 KO小鼠来检验假设 GPR39 在周细胞中上调以补偿内皮 EET 的损失，从而维持足够的 毛细血管流动并减轻与年龄相关的认知能力下降。我们将使用公正的、高通量的脂质组学来 表征脑氧脂蛋白的年龄依赖性变化，并通过磷酸蛋白质组学研究脑氧脂蛋白的变化 分离周细胞中的下游信号传导。目标 2 将确定 GPR39 在认知障碍中的作用 与慢性脑灌注不足（CCH）有关。我们将确定 GPR39 缺失是否会加剧 CCH 相关的症状 毛细血管功能障碍和认知障碍，可以通过增加 WT 中的内皮 EET 来逆转， 但不是 GPR39 KO 小鼠。目标 3 将确定 GPR39 激动剂是否可以预防认知障碍和 老年小鼠和 CCH 小鼠的毛细血管功能障碍。拟议的研究具有非常重要的技术意义 并且在概念上具有创新性，因为它们将增进对 VCI 背后机制的理解，并提出一种 与衰老相关的 VCI 的潜在新疗法。