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Brain Drain: In Vivo Optical Interrogation of Venular Function in Gray and White Matter

脑流失：灰质和白质中小静脉功能的体内光学询问

基本信息

批准号：
10463455
负责人：
Andy Y Shih
金额：
$ 245.95万
依托单位：
SEATTLE CHILDREN'S 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：
2022-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10463455
关键词：
3-Dimensional Address Adult Affect Aging Alzheimer&apos s Disease Architecture Back Blood Blood Vessels Blood capillaries Blood flow Brain Brain Drains Brain Pathology Brain region Caliber Cerebrovascular Disorders Cerebrum Clinical Clinical Research Collaborations Complement Data Dementia Deterioration Distant Drainage procedure Drug usage Etiology Exhibits Foundations Functional disorder Goals Hypoxia Image Imaging Techniques Impaired cognition Impairment Investigation Label Lead Measures Microscopy Microvascular Dysfunction Motor Cortex Mus Optics Outcome Pathology Perfusion Pericytes Pharmaceutical Preparations Pharmacology Photons Physiology Positioning Attribute Recording of previous events Resolution Rho-associated kinase Route Structure Surface System Testing Therapeutic Therapeutic Intervention Thick Tissues Transgenic Mice Venous Work age related aged arteriole awake barrel cortex cerebral capillary cerebral degeneration constriction density fasudil genetic approach gray matter imaging approach imaging study in vivo innovation insight mouse model multiphoton imaging neurovascular novel novel imaging technology novel strategies optical imaging pre-clinical preclinical study prevent serial imaging therapeutic target two-photon vascular cognitive impairment and dementia vasoconstriction venule white matter

项目摘要

PROJECT SUMMARY Much of our understanding of how cerebrovascular disease contribute to dementia focuses on the pathology of brain arterioles. However, whether pathology of cerebral venules also contribute to impairment of cerebral perfusion remains highly understudied. Preclinical and clinical studies have demonstrated marked alterations in venule tortuosity and vascular wall composition in small vessel diseases that underlie Vascular contributions to Cognitive Impairment and Dementia (VCID) and Alzheimer’s disease. Yet, the fundamentals of how brain venous networks are organized, and how their deterioration contributes to dementia, remain obscure. The goal of this project is to leverage recent advances in multi-photon imaging to investigate age-related impairment of venous drainage in deep gray and white matter of mouse brain in vivo. Cerebral white matter resides in deep brain regions and is particularly sensitive to blood flow deficit in early stages of dementia. It is challenging to access this tissue in vivo such that the etiology of white matter deficits can be better understood. Our approach overcomes this issue by using a combination of in vivo deep two-photon imaging with long wavelength excitation/emission and three-photon imaging to study microvasculature at the cortical gray-white matter interface and in deeper white matter, respectively. In preliminary studies, we found that blood drainage from deeper tissues rely exclusively on rare ascending venules, termed principle cortical venules (PCVs). PCVs collect blood by extending massive branching networks with long, tortuous draining capillaries. Critically, deep microvascular networks of PCVs were selectively constricted, reduced in vascular density, and more poorly perfused in aged mice (18-24 months) compared to adult mice (6-9 months). Our over-arching hypothesis is that deterioration of PCV structure and function is the basis for age-related blood flow impairment in deep gray and white matter. In Aim 1 of this project, we will test the hypothesis that PCVs exhibit brain region-specific deterioration in structure and function during aging, as white matter is more distant from arteriolar input in regions with thicker cortex. In Aim 2, we will test the hypothesis that dysfunction of capillary pericytes contributes to deterioration of PCV networks. In Aim 3, we will test the hypothesis that vasoconstriction and flow impairment in PCV networks can be alleviated by fasudil, a clinically-used drug that can reduce contractile tone in capillaries in addition to arterioles. A genetic strategy to remove fasudil’s target, rho kinase, specifically in brain capillary pericytes will complement the pharmacological approach. This project is significant because it will: (1) Advance novel imaging technologies to study the microvascular basis of white matter degeneration in mouse models of VCID and Alzheimer’s disease. (2) Provide insight into the structure and function of PCVs, which are an uncharacterized and essential drainage system for white matter. (3) Provide insight on how age-related pericyte dysfunction contributes to blood flow impairment, and whether they are a therapeutic target. (4) Yield data on whether age-related flow impairment in white matter is amenable to therapeutic modulation.

项目概要我们对脑血管疾病如何导致痴呆的大部分理解都集中在以下病理学上：脑动脉。然而，脑小静脉的病理学是否也会导致脑损伤？灌注仍然未被充分研究。临床前和临床研究表明，小血管疾病中的小静脉曲折和血管壁组成是血管对认知障碍和痴呆（VCID）和阿尔茨海默病。然而，脑静脉如何运作的基本原理网络的组织方式及其恶化如何导致痴呆症仍然不清楚。此举的目标该项目旨在利用多光子成像的最新进展来研究与年龄相关的损伤体内小鼠大脑深部灰质和白质的静脉引流。大脑白质位于大脑深部区域在痴呆早期对血流不足特别敏感。这是具有挑战性的进入体内该组织，以便更好地了解白质缺陷的病因。我们的方法通过结合使用体内深层双光子成像和长波长克服了这个问题激发/发射和三光子成像研究皮质灰白质的微脉管系统分别在界面和更深的白质中。在初步研究中，我们发现血液从更深的组织完全依赖于罕见的升小静脉，称为主皮质小静脉（PCV）。 PCV 通过用长而曲折的引流毛细血管延伸巨大的分支网络来收集血液。关键是，深 PCV 的微血管网络选择性收缩，血管密度降低，且更差与成年小鼠（6-9 个月）相比，老年小鼠（18-24 个月）进行灌注。我们的首要假设是 PCV结构和功能的恶化是深灰质年龄相关血流损伤的基础和白质。在该项目的目标 1 中，我们将检验 PCV 表现出大脑区域特异性的假设衰老过程中结构和功能退化，因为白质距离动脉输入区域更远具有较厚的皮质。在目标 2 中，我们将检验毛细血管周细胞功能障碍导致的假设 PCV 网络恶化。在目标 3 中，我们将检验以下假设：血管收缩和血流障碍法舒地尔可以缓解 PCV 网络中的症状，法舒地尔是一种临床使用的药物，可以降低毛细血管的收缩张力除了小动脉。一种去除法舒地尔靶点 rho 激酶（特别是脑毛细血管中的靶点）的遗传策略周细胞将补充药理学方法。该项目意义重大，因为它将：（1）推进新型成像技术研究小鼠模型白质变性的微血管基础 VCID 和阿尔茨海默病。 (2)深入了解PCV的结构和功能白质的无特征且重要的排水系统。 (3) 深入了解年龄相关的周细胞如何功能障碍会导致血流障碍，以及它们是否是治疗目标。 (4) 产量数据年龄相关的白质血流损伤是否适合治疗调节。