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.

项目摘要/摘要 尽管阿尔茨海默氏病的病理生理（AD）是复杂且多因素的，血管合并症 近三分之二的AD患者发生脑血管功能不全。但是，脑血管多么 与广告相互作用并促成广告的不足仍然知之甚少。最近，脑血管组（即 已经提出了脑内皮细胞和周细胞的转录组轮廓）作为一种概念 研究中枢神经系统疾病中的血管机制的框架。响应RFA-AG-23-014（机制） 在AD/ADRD中的脑部灌注不足），我们建议检验脑血管功能不全的假设 散布广告脑血管素，最终导致认知障碍。 正常的大脑通过诱导的内源性血管重塑和 血管生成。 AD干扰内源性血管生成和血管恢复的存在 灌注不足，这加剧了广告的进展，并使AD脑血管群恶化。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 干扰脑血管组中的昼夜节律平衡，从而干扰内源性血管生成 对灌注灌注的反应。 调查AD，血管反应和昼夜节律之间这些相互作用的重要性是 我们的试点数据强调。例如，我们在大脑的转录组轮廓上显示出更大的差异 在活动期间测试时，野生型与AD小鼠的内皮细胞和周细胞比较 到非活动（睡眠）阶段。为了检验我们的假设，我们提出了三个综合目的。 AIM 1将显示 该广告大脑在响应灌注不足的情况下表现出较低的补偿性血管生成能力，而AIM 2 将表明昼夜节律在广告大脑中被破坏，而昼夜节律抑制了 血管生成反应。最后，AIM 3将检查重新归一致的昼夜节律是否改善 AD小鼠中灌注不足后，脑血管组并促进血管生成。 脑部灌注不足后，AD大脑是否以及如何失去补偿性血管生成能力是未知的。 因此，我们设计了一个多学科的多L​​AB项目，以研究如何填补这一知识空白。 昼夜节律中的扰动破坏了脑血管组和AD中较差的灌注不良。