GPR39 as a Therapeutic Target in Aging-Related Vascular Cognitive Impairment and Dementia

项目总结 据估计，全球痴呆症患者人数为5740万，预计到2050年将增加两倍 由于世界人口老龄化，成本接近4万亿美元。增龄性血管认知功能障碍 痴呆症(VCID)是仅次于阿尔茨海默病(AD)的第二大痴呆症原因。这个 VCID的潜在机制尚不清楚，目前还没有特定的治疗方法可用于预防 或者治疗VCID。我们先前已经发现酶溶解的环氧化物的表达和活性增加。 人脑组织微血管内皮细胞水解酶活性的研究 脑部小血管疾病的痴呆和尸检组织病理学证据。转基因小鼠 内皮细胞Tie2启动子(Tie2-hsEH)作用下的人sEH基因表达呈年龄依赖性 认知缺陷，支持内皮细胞sEH上调和认知障碍之间的因果联系。Seh 负责分解14，15-环氧二十碳三烯酸酯(14，15-EET)，这是一种内源性脂质信号 具有血管扩张剂特性的分子，优先作用于小血管。我们最近确认了G 作为14，15-EET分子靶点的蛋白偶联受体39(GPR39)在人和小鼠脑中的定位 在毛细血管周细胞中。这项应用的目标是开发一流的、可穿透中枢神经系统的小分子 GPR39激动剂用于治疗VCID。我们已经完成了对一种小型- 包含超过250,000种化合物的分子文库，它们鉴定了几种有希望的化合物 高选择性、高效性和类药物特性。拟议的研究将使用多个体外和体内研究 鉴定先导化合物(Hit-to-Lead；目标1)的分析，确定它们在小鼠模型中的安全性和有效性 衰老和慢性脑低灌注(CCH；临床前测试；目标2)引起的VCID，并对其进行优化 口服生物利用度(铅优化；目标3)。拟议的研究具有非常重要的意义，具有翻译性和 创新。目前对VCID的安全有效治疗的医学需求尚未得到满足，基于 越来越多的VCID患者由于人口老龄化、缺乏疾病修正治疗以及 VCID的心理、社会和经济负担。我们建议开发一种小分子疗法， 针对VCID的新机制，涉及一种新的受体(GPR39)和细胞类型(毛细血管周细胞)。

PROJECT SUMMARY The number of individuals with dementia, estimated at 57.4 million cases worldwide, is expected to triple by 2050 at a cost approaching $4 trillion due to aging of the world population. Aging-related vascular cognitive impairment and dementia (VCID) is the second most common cause of dementia after Alzheimer's disease (AD). The mechanisms underlying VCID are not well understood, with no specific therapies currently available to prevent or treat VCID. 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 cerebral small vessel disease. 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 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 goal of this application is to develop a first-in-class, CNS-penetrant small molecule GPR39 agonist as a treatment for VCID. We have completed high-throughput screening (HTS) of a small- molecule library containing more than 250,000 compounds that identified several promising compounds with high selectivity, potency and drug-like properties. The proposed studies will use multiple in-vitro and in-vivo assays to identify lead compounds (Hit-to-Lead; Aim 1), determine their safety and efficacy in mouse models of VCID induced by aging and chronic cerebral hypoperfusion (CCH; Preclinical Testing; Aim 2), and optimize them for oral bioavailability (Lead Optimization; Aim 3). The proposed studies are highly significant, translational and innovative. There is currently an unmet medical need for a safe and effective therapy for VCID, based on the growing number of patients with VCID due to population aging, lack of disease-modifying therapy, and the psychological, social and economic burden of VCID. We propose to develop a small molecule therapeutic that targets a novel mechanism for VCID involving a novel receptor (GPR39) and cell type (peri-capillary pericytes).