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Role of Protease Activated Receptor 4 in cerebrovascular dysfunction and dementia

蛋白酶激活受体4在脑血管功能障碍和痴呆中的作用

基本信息

批准号：
10287131
负责人：
HEIDI E HAMM
金额：
$ 21.85万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287131
关键词：
Address Adult Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Anticoagulants Autopsy Behavior Behavior assessment Biological Markers Blood Blood - brain barrier anatomy Blood Platelets Blood Vessels Blood coagulation Blood flow Brain Cardiovascular Diseases Cells Cerebral Amyloid Angiopathy Cerebrovascular Disorders Cerebrum Chronic Chronic Disease Cleaved cell Clinical Coagulation Process Cognition Cognition Disorders Cognitive aging Complement Complement Activation Cytolysis DNA Dementia Deposition Development Diabetes Mellitus Drug Targeting Elderly Endothelium Epigenetic Process Evaluation Event Extracellular Matrix Extravasation F2R gene Family Fibrin Fibrinogen G-Protein-Coupled Receptors Generations Genes Genetic Genetic Variation Grant Hemostatic function Hippocampus (Brain)Homing Human Human Genetics Immune Immunity Impaired cognition Inflammation Inflammatory Investigational Therapies Knock-out Learning Ligands Link Longevity Measures Mediating Mediator of activation protein Memory Methylation Modernization Modification Mus Mutation Nerve Degeneration PAR-1 Receptor Pathologic Peptides Pharmacology Platelet Activation Play Prefrontal Cortex Process Resistance Risk Factors Role Sampling Sex Differences Site Structure Testing Therapeutic Thrombin Thrombosis Traumatic Brain Injury Vascular Dementia Vascular Diseases Vascular Smooth Muscle abeta deposition aging brain arteriole blood-brain barrier disruption brain abnormalities cerebral microvasculature chemokine cognitive function cohort cytokine demethylation epidemiology study familial Alzheimer disease human old age (65+)inflammatory marker mouse model mouse protease-activated receptor 4 neuroinflammation neuropathology neutrophil novel strategies overexpression prevent protease-activated receptor 4 religious order study response sex therapeutic target vascular cognitive impairment and dementia vascular contributions vascular inflammation vascular injury wound

项目摘要

We propose to study the role of protease-activated receptor (PAR) 4 in contributing to vascular cognitive impairment and dementia (VCID). Because traumatic brain injury is a major risk factor for AD, wounding-induced platelet activation and thrombin are at the top of a chain of events leading to fibrin deposition, microinfarcts, blood-brain barrier disruption and inflammation that may contribute to VCID. PAR4 is a platelet GPCR that is strongly activated by thrombin and only slowly inactivated, and thus contributes most of the platelet-derived thrombin, greater procoagulant microparticle formation, increased fibrin deposition, and initiation of platelet- stimulated inflammation. PAR4 is also expressed in immune cells and vasculature, and under inflammatory conditions, PAR4 is overexpressed via epigenetic demethylation of the PAR4 gene, F2RL3. PAR4 knockout studies have determined a role for PAR4 in hemostasis and thrombosis, as well as in neutrophil homing and invasion at the site of vascular insult. We have shown that higher levels of PAR4 expression in the prefrontal cortex of aging adults were associated with a faster rate of cognitive decline in a longitudinal human cohort evaluating cognitive aging, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). We also found that PAR4 is upregulated on cerebral arterioles in 5XFAD mice that express a suite of 5 mutations associated with familial AD. However, a direct test of the role of PAR4 in vascular dementia and AD pathology has never been carried out previously. In this grant, we will study the role of PAR4 both in the brains of aging humans with dementia as well as in 5XFAD mice. In Aim 1, we propose to explore the role of PAR4 human genetic variation, postmortem brain expression, and postmortem brain epigenetic alterations in the neuropathology and clinical progression of AD and VCID. In Aim 2, we will cross PAR4-/- mice with 5XFAD mice to determine if lack of PAR4 will protect against fibrin deposition and inflammation and enhance cognition. In As sex differences are present in longevity/aging, inflammation and immunity, vascular disease and dementia, all studies will be performed in both sexes. If overexpression of PAR4 increases the progression of dementia, and deletion of PAR4 can arrest or slow the development of dementia in the severe animal model 5XFAD, this will suggest that pharmacological inhibition of PAR4 might be a useful approach therapeutically, suggesting a much more in-depth evaluation of PAR4 as a pharmacological target in humans. A key role of PAR4 at the beginning of the cascade of platelet activation and initiation of inflammation would make it an excellent target for treatment of AD and vascular dementia.

我们建议研究蛋白酶激活受体（PAR） 4在血管认知中的作用