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在有助于血管认知的作用障碍和痴呆症（VCID）。因为创伤性脑损伤是AD的主要危险因素，因此受伤引起血小板激活和凝血酶位于一系列事件的顶部，导致纤维蛋白沉积，微吸收，血脑屏障的破坏和炎症可能导致VCID。 PAR4是一个血小板GPCR，是通过凝血酶强烈激活，仅缓慢灭活，因此贡献了大多数血小板衍生的凝血酶，较大的凝集剂微粒形成，纤维蛋白沉积增加以及血小板的启动刺激的炎症。 PAR4在免疫细胞和脉管系统中也表达，在炎症下也表达条件，PAR4通过PAR4基因F2RL3的表观遗传脱甲基过表达。 PAR4淘汰赛研究已经确定了PAR4在止血和血栓形成以及中性粒细胞归巢中的作用在血管侮辱的现场入侵。我们已经表明，前额叶中较高的PAR4表达水平衰老成年人的皮层与纵向人类队列中认知能力下降的速度更快有关评估认知衰老，宗教秩序研究（ROS）和RUSH记忆和衰老项目（MAP）。我们还发现，在表达5个突变的套件的5xFAD小鼠中，PAR4在脑动脉上上调与家族广告有关。但是，直接测试PAR4在血管痴呆和AD病理学中的作用以前从未进行过。在这笔赠款中，我们将研究Par4在衰老大脑中的作用患有痴呆症以及5xfad小鼠的人。在AIM 1中，我们建议探索Par4人类的作用遗传变异，死后脑表达和死后脑表观遗传改变 AD和VCID的神经病理学和临床进展。在AIM 2中，我们将用5xFAD小鼠越过PAR4 - / - 小鼠确定缺乏PAR4是否会预防纤维蛋白沉积和炎症并增强认知。在性别差异存在于寿命/衰老，炎症和免疫力，血管疾病和痴呆症中研究将在两性中进行。如果PAR4的过表达增加痴呆症的进展，并且删除PAR4可以阻止或减慢严重动物模型5xfad中痴呆的发展，这将表明对PAR4的药理抑制作用可能是一种有用的治疗方法，这表明了很多对PAR4作为人类的药理学靶标的更深入的评估。一开始Par4的关键作用血小板激活和炎症开始的级联将成为治疗的绝佳目标 AD和血管痴呆。