Mechanisms of vasomotion-mediated perivascular clearance in cerebral amyloid angiopathy

脑淀粉样血管病血管舒缩介导的血管周围清除机制

• 批准号: 10518909
• 负责人: Susanne Janneke Van Veluw
• 金额: $ 61.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518909
• 关键词: Abeta clearance; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Amyloid beta-Protein; Arteries; Automobile Driving; Blood Vessels; Blood capillaries; Brain; Calcium; Cell physiology; Cells; Cephalic; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrospinal Fluid; Cerebrovascular system; Chronic; Coupled; Coupling; Data; Dementia; Deposition; Dextrans; Disease; Disease model; Drainage procedure; Early Intervention; Elderly; Event; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genes; Hemorrhage; High Prevalence; Human; Image; Imaging Techniques; Immunotherapy; Impaired cognition; Impairment; Individual; Injections; Intercellular Fluid; Intervention; Label; Lead; Literature; Lobar; Measures; Mediating; Metabolic; Methods; Modeling; Mus; Nutrient; Oxygen; Pathway interactions; Patients; Pattern; Photic Stimulation; Physiologic pulse; Physiological; Physiology; Play; Process; Property; Research; Resolution; Rest; Risk; Role; Severities; Smooth Muscle Myocytes; Speed; System; Techniques; Testing; Time; Tracer; Transgenic Mice; Translations; Vascular Diseases; Vascular Smooth Muscle; Visual; Waste Products; Work; abeta accumulation; abeta deposition; aging brain; arteriole; awake; base; blood oxygen level dependent; brain dysfunction; brain health; brain tissue; cerebrospinal fluid flow; clinical diagnosis; design; driving force; effective therapy; experimental study; fluid flow; hemodynamics; improved; in vivo; in vivo optical imaging; innovation; mouse model; neuroimaging; new therapeutic target; non-invasive imaging; novel; optical imaging; optogenetics; particle; preservation; prevent; single-cell RNA sequencing; solute; therapeutic development; transcriptomics; translational approach; two photon microscopy; vasomotion; wasting

Project Summary / Abstract Title project: “Mechanisms of vasomotion-mediated perivascular clearance in cerebral amyloid angiopathy” The blood vessels in the brain play an important role in facilitating clearance of metabolic waste products. Impaired perivascular clearance of amyloid β (Aβ) has been implicated in the pathophysiology of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease. However, fundamental unknows including the directionality and major driving forces of perivascular clearance remain, which has hampered the development of therapeutic strategies aimed at targeting the perivascular waste clearance system. Moreover, experimental observations in mice have remain largely unexplored in the human brain. Prior work from the applicant uncovered a role for vasomotion – slow spontaneous oscillations of arterioles generated by vascular smooth muscle cells (SMCs) – as a major driving force for perivascular clearance. This project will further zoom in on vasomotion and test the novel hypothesis that targeting vascular SMCs may provide an attractive approach to enhance vasomotion and thereby facilitate perivascular Aβ clearance. This project will use CAA as a model disease to test this hypothesis, as CAA is characterized by the gradual deposition of vascular Aβ, impaired perivascular clearance, SMC degeneration, and vascular dysfunction. The aims of this project are to further unravel the physiological basis of vasomotion-mediated perivascular clearance, to determine the effect of vascular Aβ accumulation on vasomotion and clearance, to explore the potential of enhancing low frequency arteriolar oscillations as an intervention strategy to successfully clear Aβ from the brain, and to measure the coupling between low frequency hemodynamics and fluid flow in the human brain. We will use a translational approach, utilizing optical imaging techniques in awake mice coupled with direct optogenetic stimulation of vascular SMCs, as well as fast functional MRI in human individuals with and without CAA. Successful completion of these aims will improve our understanding of the physiological basis of vasomotion-mediated perivascular clearance and provide much needed proof-of-concept data to support the potential of modulating low frequency arteriolar oscillations as an early intervention strategy to promote Aβ clearance from the brain.

项目总结/摘要 标题项目：“脑淀粉样血管病中血管运动介导的血管周围清除机制” 大脑中的血管在促进代谢废物的清除方面起着重要作用。 β淀粉样蛋白（Aβ）血管周围清除障碍与脑缺血的病理生理学有关。 淀粉样血管病（CAA）和阿尔茨海默病。然而，基本的未知数，包括 血管周围清除的方向性和主要驱动力仍然存在，这阻碍了发展 针对血管周围废物清除系统的治疗策略。此外，实验 在小鼠中的观察结果在人脑中仍然基本上未被探索。申请人之前的工作 揭示了血管运动的作用-血管平滑肌产生的小动脉的缓慢自发振荡 肌肉细胞（SMC）-作为血管周围清除的主要驱动力。该项目将进一步放大 血管舒缩和测试新的假设，靶向血管平滑肌细胞可能提供一个有吸引力的方法， 增强血管舒缩，从而促进血管周围Aβ清除。本项目将使用CAA作为模型 疾病来验证这一假设，因为CAA的特征是血管Aβ逐渐沉积，受损 血管周围清除、SMC变性和血管功能障碍。该项目的目的是进一步 阐明血管舒缩介导的血管周围清除的生理基础，以确定 血管Aβ积聚对血管舒缩和清除的影响，探讨低频增强的潜力 小动脉振荡作为一种干预策略，成功地从大脑中清除Aβ，并测量 低频血液动力学和人脑中的流体流动之间的耦合。我们将使用一个平移 方法，利用清醒小鼠中的光学成像技术，结合直接光遗传刺激， 血管平滑肌细胞，以及快速功能性MRI在人类个体与CAA。成功 这些目标的完成将提高我们对血管舒缩介导的生理基础的理解。 血管周围清除率，并提供急需的概念验证数据，以支持调节 低频小动脉振荡作为早期干预策略，以促进Aβ从脑中清除。