The Role of 20-HETE in the Pathogenesis of Dementia

老龄化和高血压是脑血管疾病、中风、 血管认知障碍(VCI)和阿尔茨海默病(AD)。然而，这些基因和途径 确定遗传易感性是未知的。在初步研究中，罗曼博士的实验室确定了 抑制20-HETE形成的细胞色素P4A11和4F2基因变异与血管紧张素转换酶基因缺失有关 4,286名老年患者的海马区和AD标志区体积与认知功能障碍 社区动脉粥样硬化风险-神经认知研究(ARIC-NCS)。这些相同的变种已经被 以前与高血压和中风有关，但它们对随着年龄增长而丧失认知能力的贡献是新的。 对于产生20-HETE或表达新发现的GPR75受体的细胞，我们知之甚少。 或者衰老和高血压对这一途径表达的影响。20-HETE抑制剂有 据报道可以减弱脑血管的肌源性反应和脑血流量的自动调节 (CBF)。脑血流量的自动调节保护大脑免受毛细血管压、血脑屏障(BBB)增加的影响 渗漏，以及血压升高后的神经损伤。CBF对立面的自动调节 In压力在老年、高血压、糖尿病和AD患者中经常受损，但其在高血压发展中的作用 认知障碍仍有待确定。验证细胞色素P4A/F突变与 为了确定相关机制，罗曼博士的研究小组发现了一种同源基因 Dahl盐敏感(SS)大鼠20-HETE形成不足，并证实其存在损害 CBF的自动调节。他们还创造了基于SS遗传背景的转基因救援模型。这个项目 现在将检验这样一种假设，即20-HETE形成过程中的遗传缺陷会损害CBF 自动调节，增加大脑毛细血管的压力，促进血脑屏障渗漏、神经变性和 与年龄和/或高血压有关的认知功能障碍。我们将确定这些酶的细胞定位 在大脑中产生20-HETE及其受体，并确定野生型Cyp4A1基因在年轻人中是否敲入 老年SS大鼠恢复20-HETE的产生并保护认知发育 衰老和/或高血压所致的损害。这部作品具有极高的翻译价值，应该成为 用于开发基因测试，以确定携带CYP4A11和4F2突变的患者可能面临 认知障碍的发展。

Aging and hypertension are primary risk factors for the development of cerebral vascular disease (CVD), stroke, vascular cognitive impairment (VCI), and Alzheimer’s disease (AD). However, the genes and pathways determining genetic susceptibility are unknown. In preliminary studies, Dr. Roman’s lab identified sequence variants in t h e CYP4A11 and 4F2 genes, which inhibit the formation of 20-HETE, are associated with loss of hippocampal and AD signature region volumes, and cognitive dysfunction in 4,286 elderly patients in the Atherosclerosis Risk in Communities-Neurocognitive Study (ARIC-NCS). These same variants have been previously linked to hypertension and stroke, but their contribution to the loss of cognition with aging is novel. Little is known about the cells that produce 20-HETE or express its newly discovered GPR75 receptor in the brain or the influence of aging and hypertension on the expression of this pathway. 20-HETE inhibitors have been reported to attenuate the myogenic response of cerebral arteries and autoregulation of cerebral blood flow (CBF). Autoregulation of CBF protects the brain from increases in capillary pressure, blood-brain barrier (BBB) leakage, and neurological damage following elevations in blood pressure. Autoregulation of CBF to elevations in pressure is often impaired in elderly, hypertensive, diabetic and AD patients, but its role in the development of cognitive impairment remains to be determined. To validate the association between CYP4A/F mutations and dementia, and to determine the mechanisms involved, Dr Roman’s group identified a homologous genetic deficiency in the formation of 20-HETE in Dahl salt-sensitive (SS) rats, and confirmed they exhibit impaired autoregulation of CBF. They also created transgenic rescue models on the SS genetic background. This project will now test the hypothesis that a genetic deficiency in the formation of 20-HETE, which impairs CBF autoregulation, increases pressure to cerebral capillaries to promote BBB leakage, neurodegeneration, and cognitive dysfunction with aging and/or hypertension. We will identify the cellular localization of the enzymes that produce 20-HETE and its receptors in the brain, and determine if knock-in of the wild-type Cyp4A1 gene in young and elderly SS rats restores the production of 20-HETE and protects against the development of cognitive impairment with aging and/or hypertension. This work has exceedingly high translational value and should lead to the development of genetic tests to identify patients with CYP4A11 and 4F2 mutations that may be at risk for the development of cognitive impairment.