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

• 批准号: 10054775
• 负责人: Josh Morganti
• 金额: $ 200.65万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054775
• 关键词: Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Animal Disease Models; Animal Model; Astrocytes; Automobile Driving; Blood Vessels; Brain; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Coupling; Data; Degenerative Disorder; Dementia; Deposition; Development; Disease; Disease model; Environment; Excision; Exposure to; FDA approved; Functional disorder; Future; Gliosis; Healthcare; Human; Impaired cognition; Individual; Inflammatory; Inflammatory Response; Ischemia; Knowledge; Label; Lead; Link; Mediating; Medical; Microglia; Modality; Modeling; Multiple Sclerosis; Neuroglia; Neurological outcome; Neuronal Dysfunction; Neurons; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Population; Publishing; Recording of previous events; Recovery of Function; Research; Risk; Role; Senile Plaques; Shapes; Signal Pathway; Signal Transduction; Spinal cord injury; Synapses; Testing; Tissues; Work; abeta deposition; aged; astrogliosis; base; blood-brain barrier permeabilization; cerebrovascular; comorbidity; conditional knockout; human model; innovation; neuroinflammation; new therapeutic target; novel; response; response to injury; restraint; therapeutic target; vascular cognitive impairment and dementia; vascular contributions; vascular injury; vascular risk factor

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. Contemporary work has demonstrated a critical component to these dystrophic neuroinflammatory response of astrocytes is their utilization of canonical NFkB (RelA) signaling pathway. However, relatively little is known regarding the role of RelA in astrocytes exposed to the co-morbid degenerative milieu in VCID/AD, representing a critical knowledge gap for the field. Our overarching hypothesis for this proposal is that astrocytic RelA represents a convergent inflammatory mechanism driving dysfunctional sequelae in the comorbid VCID/AD milieu. This proposal will examine three specific aims to determine how RelA utilization by astrocytes shapes both intrinsic and non- cell autonomous dysfunctional responses to the comorbid VCID/AD degenerative environment: 1. Determine the capacity of astrocytic-RelA in propagating inflammatory phenotypes of microglia and astrocytes in comorbid VCID/AD. 2. Determine the role of astrocytic-RelA in driving cerebrovascular dysfunction in comorbid VCID/AD. 3. Determine if synaptic and cognitive dysfunction in VCID/AD is linked with RelA expression in astrocytes.

项目摘要/摘要 人类和动物模型中的多条证据表明，神经炎症通过 反应性胶质细胞增生症在血管病变的发生和发展中起关键作用。 认知障碍和痴呆(VCID)和阿尔茨海默病(AD)，潜在地表明 病理生理机制。特别是，这些神经炎的几个特征在共病中 VCID/AD动物模型与反应性星形胶质细胞的功能障碍反应有关。在 健康的大脑，众所周知，星形胶质细胞在维持多种动态平衡方面发挥着关键作用 机制。然而，作为对损伤或疾病的反应，星形胶质细胞能够迅速做出反应，在 泛指星形胶质细胞增生症，有各种神经炎性形式，最近 有证据表明，这可能会导致神经元的功能失调。当代作品展示了一种 这些星形胶质细胞营养不良神经炎性反应的关键成分是它们对规范的利用 NFkB(RelA)信号通路。然而，对relA在星形胶质细胞中的作用知之甚少。 暴露在VCID/AD的共同病态退化环境中，代表着该领域的关键知识缺口。 我们对这一提议的主要假设是，星形细胞Rela代表一个收敛的 在VCID/AD并存的环境中，炎症机制导致功能障碍后遗症。这项建议 将研究三个具体目标，以确定星形胶质细胞对relA的利用如何塑造固有的和非固有的 细胞对VCID/AD共病退变环境的自主功能障碍反应： 1.测定星形胶质细胞对小胶质细胞炎性表型的增殖能力 VCID/AD共病中的星形胶质细胞 2.明确星形细胞受体在VCID/AD并发脑血管功能障碍中的作用。 3.确定VCID/AD患者的突触和认知功能障碍是否与星形胶质细胞中relA的表达有关。