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 血管认知障碍（VCI）是仅次于阿尔茨海默氏病的第二常见痴呆原因。 VCI的最常见原因是脑小血管疾病（SVD）。 SVD的基础机制是 知识渊博，目前尚无针对预防或治疗SVD和相关VCI的特定治疗方法。 我们以前已经发现酶可溶性环氧化物水解酶（SEH）在中的表达和活性增加 死者前痴呆症患者的人脑组织的微血管内皮 SVD的死后组织病理学证据。在下面表达人Seh基因的转基因小鼠 内皮TIE2启动子（TIE2-HSEH）表现出与年龄相关的认知缺陷，支持因果关系 内皮SEH上调和认知障碍。 SEH负责14,15-的崩溃 环氧酸卫生酸酯（14,15-EET），一种内源性脂质信号分子，带有血管扩张剂和血管保护剂 优先作用于小血管的特性。我们最近确定了G蛋白偶联受体39 （GPR39）作为在毛细血管周周周围的人和小鼠大脑中定位于14,15-EET的分子靶标。 当前的提案将检验以下假设：内皮 - 周期性EET/GPR39信号发挥保护性 通过保留毛细血管血流来抵抗与衰老和SVD相关的认知障碍的作用。支持这个 假设，我们的初步数据表明，GPR39敲除小鼠（GPR39KO）表现出空间记忆不足， 人类中的GPR39 SNP与VCI的MRI标记物相关。目标 1，我们将在3、12和18个月大时使用雄性和女性WT和GPR39 KO小鼠来检验假设 该GPR39在周细胞中被上调，以弥补内皮EET的损失，以维持足够 毛细血管流量和减轻与年龄相关的认知下降。我们将使用无偏的高通量脂质组学 表征了脑Oxylipins和磷酸蛋白质组学的年龄依赖性变化，以研究 孤立的周细胞中的下游信号传导。 AIM 2将决定GPR39在认知障碍中的作用 与慢性脑灌注灌注（CCH）有关。我们将确定GPR39删除是否加剧了与CCH相关的 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。 AIM 3将确定GPR39激动剂是否可以防止认知障碍和 用CCH的老年小鼠和小鼠的毛细血管功能障碍。提出的研究非常重要，从技术上讲 从概念上创新，因为他们将提高对VCI潜在机制的理解，并提出一个 与衰老相关的VCI的潜在新疗法。