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

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.

项目概要/摘要标题项目：“脑淀粉样血管病中血管舒缩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发挥着重要作用。 β 淀粉样蛋白 (Aβ) 的血管周围清除受损与脑卒中的病理生理学有关然而，淀粉样血管病（CAA）和阿尔茨海默氏病的基本未知数。血管周围清除的方向性和主要驱动力仍然存在，这阻碍了发展旨在针对血管周围废物清除系统的治疗策略。申请人之前的工作在很大程度上尚未对小鼠的观察结果进行探索。发现了血管舒缩的作用——血管平滑肌产生的小动脉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，该项目将进一步聚焦。血管舒缩并测试新的假设，即靶向血管 SMC 可能提供一种有吸引力的方法增强血管舒缩，从而促进血管周围 Aβ 清除该项目将使用 CAA 作为模型。疾病来检验这一假设，因为 CAA 的特点是血管 Aβ 逐渐沉积，受损该项目的目的是进一步研究血管周围间隙、SMC 变性和血管功能障碍。揭示血管舒缩介导的血管周围清除的生理基础，以确定其作用血管 Aβ 积累对血管舒缩和清除的影响，探索增强低频的潜力小动脉振荡作为一种干预策略，成功清除大脑中的 Aβ，并测量我们将使用平移模型来耦合人脑中的低频血流动力学和流体流动。方法，利用清醒小鼠的光学成像技术加上直接光遗传学刺激血管 SMC 以及患有和不患有 CAA 的人类个体的快速功能 MRI 成功。完成这些目标将提高我们对血管舒缩介导的生理学基础的理解血管周围清除并提供急需的概念验证数据来支持调节的潜力低频小动脉振荡作为促进 Aβ 从大脑清除的早期干预策略。