Age influences neuropoietic signaling at the neurovascular unit following stroke

描述（由申请人提供）：年龄是中风的最大风险因素；然而大多数中风模型都使用年幼的动物。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疗法的原因。我们认为，由于不考虑年龄并关注脑血管的变化，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病之间的复杂关系中发挥着主要作用。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、神经胶质、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开，并用于建立、维持和调节大脑内的离散环境，以实现最佳的神经元功能。拟议的研究涉及 NINDS 中风进展审查小组概述的优先事项，并阐述了 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。我们的中心假设指出，年龄会导致神经生成细胞因子信号传导的变化，导致血脑屏障早期加剧破坏，随后缺血性中风和再灌注后血管恢复减弱。我们将通过三个具体目标来检验我们的中心假设。具体目标 1 将确定老年大鼠中风/再灌注损伤后神经血管单元神经生成细胞因子信号传导的变化。具体目标 2 将研究老年大鼠中风/再灌注损伤后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。我们预计该提案的结果将清楚地强调，衰老对神经生成信号产生深远影响，神经生成信号影响中风后的神经血管细胞间通讯和血脑屏障功能，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。公众健康相关性：在美国，中风是第三大死亡原因，也是导致残疾的主要原因；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最重要的单一危险因素，但大多数中风研究都是在幼年动物身上进行的。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。该拨款提案旨在评估衰老对缺血和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了解年龄在中风病因、进展和恢复中的作用。

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.