Chronic Alcohol, Dementia, and CNS Fluid Homeostasis
慢性酒精、痴呆和中枢神经系统液体稳态
基本信息
- 批准号:10467520
- 负责人:
- 金额:$ 46.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-20 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Project Summary/Abstract
Alcohol use disorder (AUD) in mid-life is a significant, independent predictor of late-life dementia, particularly
vascular cognitive impairment and dementia (VCID) that includes the common subtype cerebral amyloid
angiopathy (CAA) characterized by deposits of amyloid-β (Aβ) in the cerebral vasculature. In only one decade,
from 2005-2014, the rate of alcohol binging among the elderly rose 20% overall and by 50% in women only. The
mechanisms underlying alcohol’s toxic effects on the central nervous system (CNS) remain incompletely
understood, which limits the development of strategies targeted to reduce or prevent disease burden in heavy
drinkers with and without CAA VCID. An underlying cause of alcohol’s damaging effects on the CNS is a poorly
understood dysregulation of CNS fluid homeostasis. Preliminary evidence indicates that alcohol-associated
abnormal fluid homeostasis manifests as enlarged cerebral ventricles and altered CSF flow dynamics. In
humans, specifically, this manifests as lateral ventricular enlargement, and may reflect not only tissue loss but
also itself be contributing to tissue damage and cognitive impairment. We propose that ethanol disrupts
fundamentals of fluid homeostasis, by reducing CSF flow through the interconnected glymphatic and lymphatic
systems, through biochemical and neuroimmune alterations thereby directly damaging the tissue. The
functioning of glymphatic/lymphatic system supports fluid homeostasis and clears waste and toxins from the
brain. Our proposed studies include a comprehensive series of experiments to quantitatively analyze alcohol’s
effects on CSF secretion, glymphatic and lymphatic transport, and CSF/lymph ‘omics’ profiling in normal brain
and with CAA VCID pathology. In Aim 1, we will determine how cEtoh interferes with CSF secretion in rats
with/without VCID, using a novel MRI acquisition method to measure choroidal CSF secretion, as well as blood
perfusion of the choroid plexus and cortex. We will also implement MRI sequences to measure brain
morphometry in cEtoh-exposed rats with/without VCID and sample CSF, the meninges, and brain tissue to study
pathology and biochemical lymphatic and inflammatory factors. In Aim 2, we will assess how cEtoh affects
glymphatic-lymphatic transport, cerebral and meningeal lymphatic pathology, lymphatic waste output and
cognition in rats with/without VCID. We will use dynamic contrast-enhanced MRI and computational fluid
dynamics to measure CSF flow dynamics, glymphatic transport, and lymphatic waste drainage as affected by
cEtoh and VCID, as well on CAA pathology and cognitive decline. In Aim 3 we will study how cEtoh compromises
biochemical signaling and bio-physical changes in the CSF and lymph, including proteins that regulate fluid
volume (renin-angiotensin) and proteins functioning in ion transport/signaling (Voltage dependent calcium signal,
V-type proton ATPase and Carbonic Anhydrase). Molecular pathways that we identify can later be probed for
therapeutic benefit.
项目摘要/摘要
中期的酒精使用障碍(AUD)是晚期痴呆症的重要,独立的预测指标,尤其是
包括常见亚型脑淀粉样蛋白的血管认知障碍和痴呆(VCID)
血管病(CAA)的特征是淀粉样蛋白β(Aβ)沉积在大脑脉管系统中。在短短十年中,
从2005年至2014年,在妇女中,古老的总体上饮酒率增长了20%,而女性的酒精味率上升了50%。这
酒精对中枢神经系统(CNS)的毒性作用的机制仍然不完全
了解,这限制了针对减少或防止疾病燃烧的策略的发展
有和没有CAA VCID的饮酒者。酒精对中枢神经系统的破坏性影响的根本原因是一个很差的原因
了解CNS液体稳态的失调。初步证据表明与酒精相关
异常的液体体内稳态表现为脑室增大和CSF流动动力学的改变。在
特别是人类,这表现为侧心膨胀,并且不仅反映了组织损失,还反映了
我们建议乙醇干扰
液体体内稳态的基本原理,通过减少CSF的流经互连的糖基和淋巴管的流动
系统通过生化和神经免疫性改变,从而直接损害组织。
糖/淋巴系统的功能支持液体稳态,并清除废物和毒素
脑。我们提出的研究包括一系列全面的实验,以定量分析酒精的
对正常大脑中CSF分泌,糖基和淋巴运输以及CSF/淋巴的“ OMICS”的影响
并具有CAA VCID病理学。在AIM 1中,我们将确定CETOH如何干扰CSF的大鼠分泌
使用/没有VCID,使用一种新型的MRI采集方法来测量脉络膜CSF分泌以及血液
脉络丛和皮质的灌注。我们还将实施MRI序列以测量大脑
具有/没有VCID和样品CSF的CETOH暴露大鼠的形态计量学,脑膜和脑组织
病理和生化淋巴和炎症因子。在AIM 2中,我们将评估CETOH如何影响
淋巴淋巴运输,脑和脑膜淋巴病理学,淋巴废物输出和
具有/不具有VCID的大鼠的认知。我们将使用动态对比增强的MRI和计算流体
测量CSF流动动力学,糖基运输和淋巴废水引流的动力学
CETOH和VCID,以及CAA病理学和认知能力下降。在AIM 3中,我们将研究CETOH如何妥协
CSF和淋巴的生化信号传导和生物物理变化,包括调节液体的蛋白质
在离子传输/信号传导中起作用的体积(肾素 - 血管紧张素)和蛋白质(电压依赖性钙信号,
V型质子ATPase和碳酸酐酶)。我们可以鉴定的分子途径可以探测
治疗益处。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
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