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Therapeutic implications of purinergic receptor P2X4 in ischemic stroke

嘌呤能受体 P2X4 在缺血性中风中的治疗意义

基本信息

批准号：
10711456
负责人：
Rajkumar Verma
金额：
$ 41.47万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711456
关键词：
3xTg-AD mouse Ablation Acute Affect 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 Amyloid beta-Protein Precursor Award Behavior Behavioral Biochemical Biological Assay Brain Brain Injuries Breeding Calcium Cells Central Nervous System Cerebrovascular Disorders Cognitive Complex Data Dementia Disease Progression Elderly Exhibits Future Genetic Immune Impaired cognition Incidence Infiltration Inflammasome Inflammation Inflammatory Injury Ischemic Stroke Knock-in Knockout Mice Learning Link Macrophage Mediating Memory Microglia Molecular Morphology Mus Mutant Strains Mice Mutation Myelogenous Myeloid Cells Neurodegenerative Disorders Pathogenesis Pathway interactions Peripheral Permeability Phenotype Play Population Proteins Purinoceptor Research Role Stroke Testing Therapeutic Tissues Transgenic Mice Vascular Diseases Work attenuation behavior test cerebral atrophy cognitive change cognitive function cognitive task disease phenotype extracellular glial activation improved monocyte mouse model mutant neuroinflammation neuropathology neuroprotection pharmacologic post stroke presenilin-1 stroke recovery tau mutation young adult

项目摘要

Abstract/Summary Cerebrovascular diseases including ischemic stroke contribute to Alzheimer disease (AD) neuropathological changes, including brain atrophy and accumulation of abnormal proteins such as amyloid beta (Aβ). In the geriatric population, the incidence of dementia significantly increases after stroke. Nevertheless, the molecular links between stroke and dementia are not clearly understood but could be related to neuroinflammation. Neuroinflammation plays a key role in the pathogenesis of AD, the most prevalent form of dementia. Among the innate immune cells, brain resident microglia and infiltrated monocytes –– collectively called brain macrophages –– are the primary players in neuroinflammation. Activated brain macrophages exhibit diverse phenotypes and complex interactions during AD pathology. P2X4R, the most calcium-permeable and robust P2XR subtype present on brain macrophages, is activated by extracellular ATP. Acute activation of P2X4R on macrophages leads to inflammasome formation and thus may contribute to progressive neuroinflammation during AD progression. We previously showed that P2X4R expression and activity in myeloid cells increases swiftly and exacerbates injury after ischemic stroke. Either pharmacological inhibition or genetic deletion of P2X4R showed acute neuroprotective effects after stroke in young adult mice. P2X4R blockade reduces microglial activation and CNS infiltration of peripheral monocytes after stroke. Infiltrated monocytes from P2X4R KO mice show increased clearance of dead tissue after stroke. These data support the hypothesis that P2X4R activation of both circulating monocytes and microglia exacerbate neuroinflammation and inhibit post- stroke recovery. We will use our mouse model of myeloid cell-specific P2X4R deficiency in conjunction with 3xTG AD model to evaluate P2X4R and/or its downstream targets for the treatment of AD and AD-related dementia. In the following two aims, we want to know: 1) If P2X4R expression increases in the 3xTG AD mouse model and if its absence reduces brain damage; and 2) If deletion of P2X4R on myeloid cells improves the cognitive deficiencies that occur in AD mice with or without stroke. Regardless of the results, these simple aims will be able to identify if P2X4R plays a role in AD progression.

抽象/总结