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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：
10634727
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/10634727
关键词：
Acute Address Adenosine Triphosphate Adverse effects Affect Age Aging Animal Model Animals Anti-Inflammatory Agents Antiinflammatory Effect Area Attenuated Beds Biology Brain CCL2 gene CX3CL1 gene Calcium Cell Death Cell physiology Cells Chronic Phase Clinic Data Disease Elderly Endothelium Flow Cytometry Genetic Goals Human Immune Immune response Infiltration Inflammasome Inflammation Inflammatory Injury Intervention Ischemic Stroke Knockout Mice Macrophage Measures Mediating Medical Membrane Microglia Middle Cerebral Artery Occlusion Modeling Molecular Mus Myelogenous Myeloid Cells Peripheral Permeability Phagocytes Phase Play Proteins Purinoceptor Receptor Inhibition Recovery Recovery of Function Research Resolution Role Sorting Stroke Techniques Testing Therapeutic Tissues United States Validation Vascular Endothelial Cell Work acute stroke aged antagonist brain cell cytokine disability effective intervention efficacy evaluation efficacy testing human data immune activation improved in vivo inhibitor injury recovery insight ischemic injury long term recovery migration monocyte neuroinflammation neuroprotection new therapeutic target novel novel therapeutics pharmacologic post stroke receptor receptor expression response spatiotemporal stroke outcome stroke patient stroke recovery stroke therapy tool treatment duration uptake young adult

项目摘要

Summary: Stroke remains a leading cause of disability in the United States. Stroke is a heterogeneous multifactorial disorder. Prior attempts at developing new therapies have failed in clinics due to imperfect target validation, unrealistic therapeutic windows and lack of age appropriate models. Thus, there is an opportunity and a need to identify new medical treatment for stroke. The immune cells move to stroke area in the brain and contribute to damage. We have recently shown that the purinergic P2X4 receptor is excessively stimulated by adenosine triphosphate (ATP) released by dying brain cells during stroke. This receptor protein then causes activation of the immune cells and results in greater stroke injury. We have assembled the necessary tools such as animals lacking P2X4 receptors as well as blockers that selectively inhibit the receptor. The proposal, using these new tools, aims to investigate whether this receptor protein is a novel target to develop treatment for subjects with stroke. Our initial data suggest that blocking or deleting this receptor protein during the acute phase of stroke is beneficial. However, it is unknown how this protein works and what its potential adverse effects might be. Answering these questions is the overall goal here and should define the correct approach in pursuing a new stroke treatment

概括：中风仍然是美国残疾的主要原因。中风是一种异质性多因素因素紊乱。由于目标验证不完善，之前开发新疗法的尝试在临床上失败了，不切实际的治疗窗口和缺乏适合年龄的模型。因此，有机会和需要确定中风的新疗法。免疫细胞移动到大脑中风区域并做出贡献损坏。我们最近发现嘌呤能P2X4受体受到腺苷的过度刺激中风期间垂死的脑细胞释放三磷酸盐 (ATP)。该受体蛋白然后引起激活免疫细胞并导致更大的中风损伤。我们已经组装好了动物等必要的工具缺乏 P2X4 受体以及选择性抑制该受体的阻断剂。该提案利用这些新的工具，旨在研究这种受体蛋白是否是开发治疗患有以下疾病的受试者的新靶标中风。我们的初步数据表明，在中风急性期阻断或删除这种受体蛋白是有利。然而，目前尚不清楚这种蛋白质如何发挥作用以及其潜在的不利影响是什么。回答这些问题是这里的总体目标，并且应该定义追求新的正确方法。中风治疗