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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

Abeta clearance Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos 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

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项目摘要

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.

项目摘要 /摘要标题项目：“血管症介导的脑淀粉样血管病中血管周围清除的机制” 大脑中的血管在支持清除代谢废物产品方面起着重要作用。淀粉样β（Aβ）的血管周清除受损已与大脑的病理生理学有关淀粉样血管病（CAA）和阿尔茨海默氏病。但是，基本未知数包括仍然存在方向性和血管周围清除的主要驱动力，这阻碍了发展旨在针对周围废物清除系统的理论策略。而且，实验在人脑中，小鼠的观察仍然很大。申请人的事先工作发现了血管舒张的作用 - 血管光滑产生的小动脉振荡慢肌肉细胞（SMC） - 作为血管周期清除的主要驱动力。该项目将进一步缩小血管症和检验新的假设，即靶向血管SMC可能会提供有吸引力的方法增强血管舒张症，从而成为血管周围Aβ清除率。该项目将使用CAA作为模型疾病检验该假设，因为CAA的特征是血管Aβ的等级沉积物受损血管周围清除率，SMC变性和血管功能障碍。该项目的目的是进一步阐明血管症介导的周围血管清除的物理基础，以确定血管Aβ在血管症和间隙上积累，以探索增强低频的潜力小动脉振荡作为一种干预策略，可成功地从大脑中清除Aβ，并测量低频血液动力学和人脑流体流量之间的耦合。我们将使用翻译方法，在清醒小鼠中使用光学成像技术以及直接的光遗传刺激有或没有CAA的人体中的血管SMC以及快速功能性MRI。成功的这些目标的完成将提高我们对血管症介导的物理基础的理解血管周围清除并提供急需的概念验证数据，以支持调节的潜力低频艺术级振荡作为一种早期干预策略，可促进大脑的Aβ清除率。