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.

衰老和高血压是发展脑血管疾病（CVD），中风，血管认知障碍（VCI）和阿尔茨海默氏病（AD）。但是，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序列抑制20-HETE形成的T H E CYP4A11和4F2基因中的变体与丧失海马和AD签名区域量以及4,286名患者的认知功能障碍社区神经认知研究（ARIC-NCS）的动脉粥样硬化风险。这些变体已经以前与高血压和中风有关，但是它们对衰老认知丧失的贡献是新颖的。关于产生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途径表达的影响。 20-Hete抑制剂具有据报道会减弱脑动脉的肌源性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管压力，血脑屏障（BBB）的增加血压升高后泄漏和神经损害。 CBF至海拔的自动调节在老式，高血压，糖尿病和AD患者中，压力通常会受到损害，但其在发展中的作用认知障碍仍有待确定。验证CYP4A/F突变与痴呆症，并确定涉及的机制，罗曼博士的小组确定了同源的通用 Dahl盐敏感（SS）大鼠的20-HETE形成不足，并确认它们暴露于障碍 CBF自动调节。他们还在SS遗传背景上创建了转基因救援模型。这个项目现在将检验以下假设：在20-HETE的形成中遗传缺乏症会损害CBF 自动调节，增加脑毛细管的压力，以促进BBB泄漏，神经变性和衰老和/或高血压的认知功能障碍。我们将确定酶的细胞定位在大脑中产生20-HETE及其接收器，并确定Young中野生型CYP4A1基因是否敲入 SS大鼠较早地恢复了20-HETE的产生，并防止了认知的发展衰老和/或高血压的损害。这项工作具有极高的翻译价值，应该领导开发基因检测，以识别患有CYP4A11和4F2突变的患者认知障碍的发展。