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Age influences neuropoietic signaling at the neurovascular unit following stroke

年龄影响中风后神经血管单元的神经生成信号

基本信息

批准号：
8246426
负责人：
JASON D HUBER
金额：
$ 31.41万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8246426
关键词：
Accounting Acute Address Affect Age Aging Aging-Related Process Animals Apoptosis Applications Grants Area Arthritis Atherosclerosis Attention Attenuated Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain CCL2 gene Cause of Death Cell Communication Cells Cerebrovascular Circulation Cerebrum Chronic Communities Complex Cytokine Signaling Elements Endothelium Environment Etiology Extracellular Matrix Failure Functional disorder Goals Growth Health Human Infarction Inflammation Inflammatory Interleukin-6 Investigation Ischemia Ischemic Stroke JAK2 gene Lead Malignant Neoplasms Mission Modeling Morbidity - disease rate National Institute of Neurological Disorders and Stroke Neuraxis Neuroglia Neurons Neuropoietic Cytokine Neuroprotective Agents Pericytes Permeability Phase Play Process Progress Review Group Quality of life Rattus Recovery Reperfusion Injury Reperfusion Therapy Research Risk Factors Role STAT3 gene Screening procedure Signal Transduction Stimulus Stroke Testing Therapeutic Translating United States Vascular Diseases Work age related aged angiogenesis brain circulation capillary density design disability effective therapy frailty functional outcomes improved juvenile animal mortality neurovascular unit novel therapeutic intervention overexpression response

项目摘要

DESCRIPTION (provided by applicant): Age is the single greatest risk factor for stroke; yet most stroke models use younger animals. Stroke involves changes in the cerebrovasculature; yet research is predominantly focused on therapeutics that protect neurons. These incongruities in stroke research may, in part, explain the failure of successful neuroprotectants in animal studies to translate into clinically effective therapies. We argue that by not accounting for age and focusing on changes in the cerebrovasculature, the stroke community has overlooked a vast area of potential therapeutic growth. Neuropoietic cytokines play a primary role in the complex relationship between aging and chronic morbidity; yet, little attention has been focused on age- related changes in neuropoietic cytokine activity in the brain. The blood-brain barrier (BBB) is the functional element of the neurovascular unit, an extensive network comprised of endothelium, glia, pericytes, neurons, and extracellular matrix. The BBB partitions the systemic circulation from the brain parenchyma and serves to establish, maintain, and regulate discrete environments within the brain for optimal neuronal function. The proposed studies address priorities outlined in the NINDS Stroke Progress Review Group and speak to the missions of both NINDS and NIA. Our long term goal is to improve functional outcomes of people who have a stroke. Our central hypothesis states age contributes to changes in neuropoietic cytokine signaling resulting in an early, exacerbated disruption of the BBB followed by attenuated vascular recovery after ischemic stroke and reperfusion. We will test our central hypothesis with three specific aims. Specific aim 1 will determine changes in neuropoietic cytokine signaling at the neurovascular unit in aged rats following stroke/reperfusion injury. Specific Aim 2 will investigate changes in neuropoietic cytokine signaling on size and localization of BBB disruption in aged rats following stroke/reperfusion injury. Specific Aim 3 will assess changes in neuropoietic cytokine signaling on cerebral microvasculature recovery in aged rats following stroke/reperfusion injury. We expect the results from this proposal will clearly highlight that aging has profound effects on neuropoietic signaling that influences neurovascular cell-cell communication and BBB function following stroke that must be taken into account when developing and screening therapeutics to reduce morbidity and mortality. PUBLIC HEALTH RELEVANCE: In the United States, stroke is the third leading cause of death and the leading cause of disability; yet effective treatments for people suffering a stroke have not materialized. We contend that age is the single most important risk factor for stroke but most stroke research is being conducted on young animals. Furthermore, most stroke research is focused on rescuing and protecting neurons; yet, stroke is a vascular disease. This grant proposal is designed to evaluate the influence aging has on BBB function following ischemia and reperfusion. Our results will lead to a better understanding of the role age, plays in stroke etiology, progression, and recovery.

描述（由申请人提供）：年龄是卒中的单一最大风险因素;但大多数卒中模型使用较年轻的动物。中风涉及脑血管系统的变化;然而研究主要集中在保护神经元的治疗上。中风研究中的这些不一致可能部分解释了动物研究中成功的神经保护剂未能转化为临床有效的治疗方法。我们认为，由于不考虑年龄因素，而只关注脑血管系统的变化，卒中社区忽视了潜在治疗增长的广阔领域。神经生成细胞因子在衰老和慢性病之间的复杂关系中起主要作用;然而，很少关注脑中神经生成细胞因子活性的年龄相关变化。血脑屏障（BBB）是神经血管单位的功能元件，神经血管单位是由内皮细胞、胶质细胞、周细胞、神经元和细胞外基质组成的广泛网络。BBB将体循环与脑实质分隔开，并用于建立、维持和调节脑内的离散环境以实现最佳神经元功能。拟议的研究解决了NINDS卒中进展审查小组中概述的优先事项，并与NINDS和NIA的任务相一致。我们的长期目标是改善中风患者的功能结果。我们的中心假设指出，年龄有助于神经生成细胞因子信号传导的变化，导致缺血性卒中和再灌注后早期、加重的BBB破坏，随后是减弱的血管恢复。我们将以三个具体目标来检验我们的中心假设。具体目标1将确定中风/再灌注损伤后老年大鼠神经血管单位神经生成细胞因子信号传导的变化。具体目标2将研究脑卒中/再灌注损伤后老年大鼠中神经生成细胞因子信号传导对BBB破坏的大小和定位的变化。具体目标3将评估中风/再灌注损伤后老年大鼠脑微血管恢复中神经生成细胞因子信号传导的变化。我们预计这项提案的结果将清楚地强调，衰老对影响脑卒中后神经血管细胞间通讯和BBB功能的神经生成信号传导具有深远的影响，在开发和筛选治疗方法以降低发病率和死亡率时必须考虑到这一点。公共卫生相关性：在美国，中风是第三大死亡原因和残疾的主要原因;然而，对中风患者的有效治疗尚未实现。我们认为年龄是中风的最重要的危险因素，但大多数中风研究都是在年轻动物身上进行的。此外，大多数中风研究都集中在拯救和保护神经元上;然而，中风是一种血管疾病。这项资助计划旨在评估缺血和再灌注后衰老对BBB功能的影响。我们的研究结果将有助于更好地理解年龄在卒中病因、进展和恢复中的作用。