The Role of 20-HETE in the Pathogenesis of Dementia

20-HETE 在痴呆发病机制中的作用

基本信息

批准号：
10192612
负责人：
Ezekiel Gonzalez-Fernandez
金额：
$ 3.97万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192612
关键词：
Acute Aging Albumins Alkane 1-monooxygenase Alzheimer&apos s Disease Alzheimer&apos s disease patient Animal Model Atherosclerosis Risk in Communities Attenuated Blood - brain barrier anatomy Blood Pressure Blood capillaries Brain CYP4A1 gene Caliber Cell Count Cells Cerebrovascular Circulation Cerebrovascular Disorders Chromosome 5 Chronic Cognition Consomic Strain Dahl Hypertensive Rats Dementia Development Elderly Enzymes Essential Hypertension Evans blue stain Exhibits Extravasation GPR75 gene Genes Genetic Genetic Predisposition to Disease Hippocampus (Brain)Histology Homeostasis Hydroxyeicosatetraenoic Acids Hypertension Immunohistochemistry Impaired cognition Impairment Knock-in Lead Link Modeling Monitor Mutation Nerve Degeneration Nervous System Trauma Neurocognitive Pathogenesis Pathway interactions Patients Perfusion Production Proteins Rattus Rattus norvegicus Reporting Risk Risk Factors Role Stroke Structure Testing Transgenic Organisms Variant Vascular Cognitive Impairment Western Blotting Work arm behavior test cell type cerebral artery cerebral capillary cerebral hemodynamics cognitive development cognitive function density diabetic genetic testing inhibitor/antagonist liquid chromatography mass spectrometry loss of function motor deficit novel older patient pressure receptor response salt sensitive water maze

项目摘要

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.

衰老和高血压是脑血管疾病（CVD）、中风、然而，血管性认知障碍（VCI）和阿尔茨海默病（AD）的基因和途径。确定遗传易感性的因素尚不清楚。在初步研究中，罗曼博士的实验室确定了序列。 CYP4A11 和 4F2 基因中的变异可抑制 20-HETE 的形成，与 4,286 名老年患者的海马和 AD 特征区域体积以及认知功能障碍社区动脉粥样硬化风险-神经认知研究（ARIC-NCS）也有这些相同的变体。以前与高血压和中风有关，但它们对随着衰老而丧失认知能力的影响是新颖的。对于在细胞中产生 20-HETE 或表达其新发现的 GPR75 受体的细胞知之甚少。大脑或衰老和高血压对该通路20-HETE抑制剂的表达有影响。据报道可以减弱脑动脉的生肌反应和脑血流的自动调节 (CBF) CBF 的自动调节可保护大脑免受毛细血管压力、血脑屏障 (BBB) 的增加。血压升高后渗漏和神经损伤。老年人、高血压、糖尿病和阿尔茨海默氏症患者的压力经常受到损害，但它在疾病发展中的作用认知障碍仍有待确定，以验证 CYP4A/F 突变与认知障碍之间的关联。痴呆症，并确定所涉及的机制，罗曼博士的小组确定了同源基因 Dahl 盐敏感 (SS) 大鼠中 20-HETE 形成缺陷，并证实它们表现出受损他们还在 SS 遗传背景上创建了转基因救援模型。现在将检验 20-HETE 形成中的遗传缺陷会损害 CBF 的假设自我调节，增加脑毛细血管的压力，促进血脑屏障渗漏、神经退行性变和衰老和/或高血压引起的认知功能障碍我们将确定酶的细胞定位。在大脑中产生 20-HETE 及其受体，并确定是否在年轻人中敲入野生型 Cyp4A1 基因老年 SS 大鼠恢复 20-HETE 的产生并防止认知发展这项工作具有极高的转化价值，应该具有引领作用。开发基因测试来识别可能有 CYP4A11 和 4F2 突变风险的患者认知障碍的发展。