The effect of circadian rhythm disruptions on the angiogenic response to hypoperfusion in the AD brain

昼夜节律紊乱对 AD 大脑低灌注血管生成反应的影响

• 批准号: 10656133
• 负责人: Ken Arai
• 金额: $ 77.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656133
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Blood Vessels; Brain; Carotid Stenosis; Cell Culture Techniques; Central Nervous System Diseases; Cerebrovascular Circulation; Cerebrovascular Insufficiency; Chronic; Circadian Dysregulation; Circadian Rhythms; Common carotid artery; Compensation; Complex; Data; Dependence; Disease Progression; Endothelial Cells; Endothelium; Exhibits; Female; Functional disorder; Genes; Homeostasis; Impaired cognition; Impairment; In Vitro; Knock-out; Knockout Mice; Knowledge; Measures; Mediating; Methods; Mus; Optical Coherence Tomography; Outcome; Pathology; Pericytes; Peripheral; Phase; Physiological; Recovery; Sleep; Testing; Vascular remodeling; age group; angiogenesis; awake; brain endothelial cell; cell type; cerebral hypoperfusion; circadian; circadian pacemaker; cognitive function; comorbidity; design; experimental study; hypoperfusion; improved; in vivo; male; mouse model; multidisciplinary; novel; object recognition; response; transcriptome; transcriptome sequencing; two photon microscopy

PROJECT SUMMARY/ABSTRACT Although the pathophysiology of Alzheimer’s Disease (AD) is complex and multifactorial, vascular comorbidities and cerebrovascular insufficiency occur in almost two-thirds of AD patients. However, how cerebrovascular insufficiency interacts with and contributes to AD remains poorly understood. Recently, the brain vasculome (i.e. transcriptome profiles of cerebral endothelial cells and pericytes) has been proposed as a conceptual framework to investigate vascular mechanisms in CNS diseases. In response to RFA-AG-23-014 (Mechanisms of Brain Hypoperfusion in AD/ADRD), we propose to test the hypothesis that cerebrovascular insufficiency perturbs the AD brain vasculome, eventually leading to cognitive impairment. The normal brain compensates for hypoperfusion by inducing endogenous vascular remodeling and angiogenesis. The presence of AD interferes with endogenous angiogenesis and vascular recovery in response to hypoperfusion, and this exacerbates AD progression and worsens the AD brain vasculome. Because circadian rhythms and circadian genes are known to regulate angiogenesis, we further hypothesize that AD disrupts circadian homeostasis in the brain vasculome, thus interfering with the endogenous angiogenic response to hypoperfusion. The importance of investigating these interactions between AD, vascular responses, and circadian rhythms is emphasized by our pilot data. For example, we show a greater difference in transcriptome profiles of cerebral endothelial cells and pericytes of wild-type vs AD mice when tested during the active (awake) phase compared to the inactive (sleep) phase. For testing our hypotheses, we propose three integrated aims. Aim 1 will show that AD brains exhibit a lower capacity of compensatory angiogenesis in response to hypoperfusion, and Aim 2 will show that circadian rhythms are disrupted in AD brains and that disrupted circadian rhythms suppress angiogenic response. And finally, Aim 3 will examine whether re-normalizing circadian rhythms improves the brain vasculome and promotes angiogenesis after hypoperfusion in AD mice. Whether and how AD brains lose compensatory angiogenesis capacity after cerebral hypoperfusion is unknown. Therefore, we have designed a multi-disciplinary multi-lab project to fill this gap of knowledge by examining how perturbations in circadian rhythms disrupt the brain vasculome and worsen hypoperfusion in AD.

项目总结/摘要 虽然阿尔茨海默病（AD）的病理生理学是复杂的和多因素的， 和脑血管功能不全发生在几乎三分之二的AD患者中。然而，如何脑血管 营养不足与AD相互作用并导致AD的原因仍然知之甚少。最近，脑血管（即， 脑内皮细胞和周细胞的转录组谱）已被提出作为一个概念， 研究中枢神经系统疾病血管机制的框架。响应RFA-AG-23-014（机制 AD/ADRD中脑灌注不足），我们建议检验脑血管功能不全 干扰AD脑血管，最终导致认知障碍。 正常脑通过诱导内源性血管重塑来补偿灌注不足， 血管生成AD的存在干扰内源性血管生成和血管恢复， 到低灌注，这加剧了AD的进展，并破坏了AD脑血管。因为 已知昼夜节律和昼夜节律基因调节血管生成，我们进一步假设AD 破坏脑血管中的昼夜平衡，从而干扰内源性血管生成。 对低灌注的反应。 研究AD、血管反应和昼夜节律之间的这些相互作用的重要性是 我们的试点数据显示。例如，我们发现大脑中的转录组谱存在更大的差异， 当在活动（清醒）期测试时，野生型与AD小鼠的内皮细胞和周细胞比较 睡眠（Sleep）阶段为了验证我们的假设，我们提出了三个综合目标。目标1将显示 AD脑对低灌注表现出较低的代偿性血管生成能力， 将显示AD大脑的昼夜节律被打乱，而打乱的昼夜节律抑制了 血管生成反应最后，目标3将检查重新正常化的昼夜节律是否改善了 在AD小鼠低灌注后，脑血管组织和促进血管生成。 脑灌注不足后AD脑是否以及如何失去代偿性血管生成能力尚不清楚。 因此，我们设计了一个多学科多实验室项目，通过研究如何填补这一知识空白， 昼夜节律的扰动破坏了AD中的脑血管并使灌注不足恶化。