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Inflammatory contributions of astrocytic RelA in comorbid VCID/AD

星形胶质细胞 RelA 在 VCID/AD 共病中的炎症作用

基本信息

批准号：
10401633
负责人：
Josh Morganti
金额：
$ 35.45万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401633
关键词：
Administrative Supplement Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Amyloid beta-Protein Animal Disease Models Animal Model Astrocytes Automobile Driving Award Blood Vessels Brain Cells Cerebrovascular Circulation Cerebrovascular Disorders Chronic Circadian Dysregulation Clinical Coupling Data Degenerative Disorder Dementia Deposition Development Disease Disease model Elderly Excision Exposure to FDA approved Functional disorder Future Genetic Transcription Gliosis Healthcare Heterogeneity Human Impaired cognition Individual Inflammatory Inflammatory Response Ischemia Knowledge Label Lead Link Mediating Medical Microglia Modality Modeling Morphology Multiple Sclerosis Neuroglia Neurological outcome Neuronal Dysfunction Neurons Parents Pathogenesis Pathologic Pathology Pathway interactions Patients Phenotype Play Population Publishing Recording of previous events Recovery of Function Research Risk Role Senile Plaques Signal Pathway Signal Transduction Sleep Disorders Sleep Fragmentations Sleep disturbances Spinal cord injury Synapses Testing Tissues Work abeta deposition aged astrogliosis base blood-brain barrier permeabilization cerebrovascular cognitive function comorbidity conditional knockout human model innovation neuroinflammation new therapeutic target novel parent grant response response to injury restraint therapeutic target vascular cognitive impairment and dementia vascular contributions vascular injury vascular risk factor

项目摘要

PROJECT SUMMARY/ABSTRACT Multiple lines of evidence in both humans and animal models suggest that neuroinflammation, mediated via reactive gliosis, plays a critical role associated with the initiation and progression of vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD), potentially suggesting convergent pathophysiological mechanisms. In particular, several of these neuroinflammatory hallmarks in comorbid VCID/AD animal models have been linked with the dysfunctional responses of reactive astrocytes. In the healthy brain, it is well known that astrocytes play a critical role in maintaining a variety of homeostatic mechanisms. However, as a response to injury or disease, astrocytes are able to rapidly respond, in a generalized description referred as astrogliosis, with a variety of neuroinflammatory modalities, which recent evidence suggests may cause dysfunctional responses of neurons. Sleep disturbances/circadian disruption is a key clinical issue in dementia patients. Between 40 and 70% of older adults suffer from sleep disturbances or disorders, which are especially prevalent among patients with Alzheimer's Disease and Alzheimer’s Disease Related Dementias (AD/ADRD), such as VCID. The purpose of this one-year administrative supplement is to facilitate new collaborative research between the Morganti and Duncan labs to better understand the bi- directional relationship between chronic sleep disturbances/circadian disruption and VCID pathogenesis in the context of inflammatory mechanisms of astrocytes. This proposal will examine 2 focused specific aims, which are extensions of our ongoing projects in the parent grant RF1NS118558: 1. Determine the extent to which chronic sleep fragmentation drives astrocyte-specific inflammatory heterogeneity in the context of VCID, and whether removal astrocytic-RelA disrupts these transcriptional and morphological phenotypes. 2. Determine the extent to which chronic sleep fragmentation alters cognitive function, and whether removal astrocytic-RelA disrupts these phenotypes.

项目概要/摘要人类和动物模型中的多种证据表明，神经炎症通过反应性神经胶质增生，在血管贡献的启动和进展中发挥着关键作用认知障碍和痴呆（VCID）和阿尔茨海默病（AD），可能表明趋同病理生理机制。特别是，共病中的一些神经炎症标志 VCID/AD 动物模型与反应性星形胶质细胞的功能失调反应有关。在健康的大脑，众所周知，星形胶质细胞在维持多种稳态方面发挥着至关重要的作用机制。然而，作为对损伤或疾病的反应，星形胶质细胞能够快速做出反应广义的描述称为星形胶质细胞增生，具有多种神经炎症模式，最近有证据表明可能会导致神经元反应失调。睡眠障碍/昼夜节律紊乱是痴呆症患者的一个关键临床问题。 40% 至 70% 的老年人患有睡眠障碍或疾病，在阿尔茨海默病和阿尔茨海默病患者中尤其普遍相关痴呆症 (AD/ADRD)，例如 VCID。这项为期一年的行政补充的目的是促进 Morganti 和 Duncan 实验室之间的新合作研究，以更好地了解双慢性睡眠障碍/昼夜节律紊乱与 VCID 发病机制之间的方向关系星形胶质细胞炎症机制的背景。该提案将审查 2 个重点具体目标，即是我们在母基金 RF1NS118558 中正在进行的项目的扩展： 1. 确定慢性睡眠碎片化在多大程度上驱动星形胶质细胞特异性炎症 VCID背景下的异质性，以及去除星形胶质细胞-RelA是否会破坏这些转录和形态表型。 2. 确定慢性睡眠碎片化改变认知功能的程度，以及是否去除星形胶质细胞-RelA 会破坏这些表型。