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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：
9906421
负责人：
Ezekiel Gonzalez-Fernandez
金额：
$ 3.92万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906421
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、