Age influences neuropoietic signaling at the neurovascular unit following stroke

描述(由申请人提供)：年龄是中风的单一最大风险因素；然而大多数中风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疗法上。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，而专注于脑血管的变化，中风社区忽视了潜在的治疗增长的广阔领域。神经营养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，很少有人关注与年龄相关的脑内神经营养因子活性的变化。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、神经胶质细胞、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，用于建立、维持和调节大脑内离散的环境，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的任务。我们的长期目标是改善中风患者的功能结果。我们的中心假说认为，年龄导致神经生成细胞因子信号的改变，导致早期、加重的血脑屏障破坏，随后是缺血性卒中和再灌注后血管恢复减弱。我们将用三个具体目标来检验我们的中心假设。特定目的1将确定老年大鼠卒中/再灌注损伤后神经血管单位神经营养因子信号的变化。特定目的2将研究神经营养因子信号在老年大鼠卒中/再灌注损伤后血脑屏障破坏的大小和位置上的变化。具体目标3将评估神经生成细胞因子信号在老年大鼠中风/再灌注损伤后脑微血管恢复中的变化。我们预计，这项提案的结果将明确强调，衰老对神经生成信号具有深远的影响，从而影响中风后的神经血管细胞-细胞通讯和血脑屏障功能，在开发和筛选治疗药物以降低发病率和死亡率时必须考虑到这一点。与公共卫生相关：在美国，中风是第三大死亡原因和第一大致残原因；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唯一最重要的危险因素，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抢救和保护神经元上；然而，中风是一种血管疾病。本研究旨在评估衰老对脑缺血再灌流后血脑屏障功能的影响。我们的结果将有助于更好地理解年龄在卒中病因、进展和康复中所起的作用。

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.