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传导

• 批准号: 8048980
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048980
• 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

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）：年龄是中风的最大危险因素；然而，大多数中风模型使用的是更年轻的动物。中风涉及脑血管系统的改变；然而，研究主要集中在保护神经元的治疗方法上。中风研究中的这些不一致可能在一定程度上解释了动物实验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，由于不考虑年龄和关注脑血管系统的变化，中风界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疾病之间的复杂关系中起主要作用；然而，很少有人关注大脑中神经生成细胞因子活性与年龄相关的变化。血脑屏障（BBB）是神经血管单元的功能元件，是一个由内皮细胞、胶质细胞、周细胞、神经元和细胞外基质组成的广泛网络。血脑屏障将体循环从脑实质中分离出来，并用于建立、维持和调节脑内离散的环境，以实现最佳的神经元功能。拟议的研究涉及NINDS卒中进展审查小组概述的优先事项，并涉及NINDS和NIA的使命。我们的长期目标是改善中风患者的功能结果。我们的中心假设认为，年龄有助于神经生成性细胞因子信号的变化，导致缺血性卒中和再灌注后血管恢复减弱，从而导致血脑屏障的早期、加重破坏。我们将用三个具体目标来检验我们的中心假设。特异性目的1将确定老年大鼠脑卒中/再灌注损伤后神经血管单元神经生成性细胞因子信号的变化。特异性目的2将研究脑卒中/再灌注损伤后老龄大鼠脑屏障破坏大小和定位的神经生成性细胞因子信号的变化。特异性目的3将评估脑卒中/再灌注损伤后老年大鼠脑微血管恢复中神经生成性细胞因子信号的变化。我们希望这项研究的结果能够清楚地强调，衰老对中风后影响神经血管细胞通讯和血脑屏障功能的神经生成信号有深远的影响，这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。公共卫生相关性：在美国，中风是第三大死亡原因和致残原因；然而，对中风患者有效的治疗方法尚未出现。我们认为年龄是中风的唯一最重要的危险因素，但大多数中风研究都是在年轻的动物身上进行的。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。本拨款申请旨在评估衰老对缺血再灌注后血脑屏障功能的影响。我们的研究结果将有助于更好地理解年龄在中风病因、进展和恢复中的作用。