Investigating the microvascular mechanisms of O2 supply-demand mismatch in small vessel disease using novel high-resolution optical imaging

使用新型高分辨率光学成像研究小血管疾病中 O2 供需不匹配的微血管机制

• 批准号: 9913907
• 负责人: Cenk Ayata
• 金额: $ 70.76万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9913907
• 关键词: Alzheimer' s disease related dementia; Amyloid; Animal Genetics; Animal Model; Antibodies; Area; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Diseases; Brain region; CADASIL; Cerebral small vessel disease; Cerebrovascular Circulation; Clinical; DTR gene; Data; Dementia; Diffusion; Disease; EGF gene; Epidermal Growth Factor Receptor; Equilibrium; Erythrocytes; Exhibits; Functional disorder; Genetic; Heterogeneity; Hyperemia; Hypertension; Hypoxia; Imaging Device; Immunologics; Impaired cognition; Impairment; Inherited; Knowledge; Light; Link; Maps; Measurement; Measures; Microscopy; Microvascular Dysfunction; Modeling; Molecular; Morphology; Mus; Mutation; NOTCH3 gene; Optical Coherence Tomography; Optics; Oxygen; Passive Immunization; Pathway interactions; Perfusion; Pericytes; Pharmacology; Publishing; Research; Resolution; Rest; Signal Transduction; Smooth Muscle Myocytes; Stroke; Structural defect; Structure; TIMP3 gene; Testing; Time; Tissues; Transgenic Mice; Transgenic Model; Trees; Vascular Smooth Muscle; Work; age related; arteriole; awake; base; brain tissue; clinically relevant; disability; gray matter; hemodynamics; human disease; human model; innovative technologies; insight; islet; metabolic rate; mouse model; multimodality; mutant; novel; novel imaging technology; optical imaging; progressive neurodegeneration; response; therapy development; tissue degeneration; tissue oxygenation; tool; two photon microscopy; vascular cognitive impairment and dementia; white matter

PROJECT SUMMARY/ABSTRACT Despite intense research, we lack even the most basic understanding of how structural and functional changes in small vessel diseases of the brain (SVD) are linked to tissue oxygenation, whether this results in tissue hypoxia (O2 supply-demand mismatch), and how different microvascular segments contribute to this mismatch in different brain areas. Leveraging our cutting-edge optical imaging tools for absolute pO2, blood flow, Ca2+ signaling, and microvascular morphology, and a clinically relevant CADASIL mouse model, we propose to examine for the first time a causal link between microvascular dysfunction and O2 supply-demand mismatch. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is the most common monogenic inherited form of SVD leading to dementia, caused by mutations in Notch3. Transgenic models of CADASIL recapitulate many clinical and histopathological hallmarks of the disease, including early signs of SVD such as impaired CBF and functional hyperemic responses, and functional and structural abnormalities in both arterioles and capillaries. We will quantify absolute intravascular and tissue pO2, metabolic rate of O2 (CMRO2), CBF and capillary red blood cell flux, and microvascular morphology, at rest and during functional brain activation, in both gray and white matter, longitudinally over months, in unanesthetized CADASIL transgenic mice. Aim 1 will test whether CADASIL causes age-dependent O2 supply-demand mismatch, manifested in islets of tissue hypoxia at rest or during functional activation. Combining two-photon microscopy and optical coherence tomography (OCT), we will test whether CADASIL leads to abnormal capillary red blood cell flux and increased capillary transit time heterogeneity causing O2 supply-demand mismatch even before a reduction in absolute CBF becomes manifest. Finally, we will examine whether O2 supply-demand mismatch can be corrected by genetic, pharmacological, and immunological manipulations. Aim 2 will test whether CADASIL causes Ca2+ dysregulation in vascular smooth muscle and pericytes and whether it can be corrected by genetic, pharmacological and immunological manipulations. Aim 3 will integrate the measurements from Aims 1 and 2 and construct a numerical model of oxygen advection and diffusion based on measured microvascular morphology, reactivity, perfusion, and oxygenation. The model will relate structural and functional microvascular changes to tissue O2 supply-demand mismatch, quantify the contribution and predict the limits of the arteriolar and capillary compartments to support tissue oxygenation below which O2 supply-demand mismatch develops. The model will thus shed light on all other SVDs (e.g. hypertension, amyloid). Altogether, this proposal aims to fill significant gaps in our understanding of the mechanisms of microvascular dysfunction in CADASIL, and will inform the vascular mechanisms of progressive neurodegeneration and cognitive impairment in more common forms of SVD as well as in Alzheimer’s disease and related dementias.

项目摘要/摘要 尽管进行了激烈的研究，但我们对结构和功能的变化方式缺乏最基本的理解 在大脑的小血管疾病中（SVD）与组织氧合有关，这是否导致组织 缺氧（O2供需不匹配），以及不同的微血管段如何贡献此不匹配 在不同的大脑区域。利用我们的尖端光学成像工具用于绝对PO2，血流，Ca2+ 信号传导和微血管形态以及临床相关的卡达西尔小鼠模型，我们建议 首次检查微血管功能障碍与O2供需不匹配之间的因果关系。 CADASIL（脑常染色体显性动脉炎，皮质下肌病和白血病）是 由Notch3突变引起的最常见的SVD遗传形式导致痴呆。 Cadasil的转基因模型概括了许多临床和组织病理学标志， 包括SVD的早期迹象，例如CBF受损和功能性高血压反应，功能性和功能性和 动脉和毛细血管的结构异常。 我们将量化绝对血管内和组织PO2，O2的代谢率（CMRO2），CBF和毛细血管红色 血细胞通量和微血管形态，在灰色和功能性脑激活期间，灰色和灰色 白质，在几个月内纵向，在未经麻醉的Cadasil转基因小鼠中。 AIM 1将测试是否 卡达西尔引起年龄依赖性的O2供求不匹配，在静止或 在功能激活期间。将两光子显微镜和光学相干断层扫描（OCT）相结合，我们 将测试卡达西尔是否导致异常毛细血管红细胞通量和增加毛细管过渡时间 甚至在减少绝对CBF之前，引起O2供求不匹配的异质性不匹配 显现。最后，我们将检查是否可以通过遗传来纠正O2供需不匹配， AIM 2将测试Cadasil是否引起Ca2+ 血管平滑肌和周细胞的失调以及是否可以通过遗传纠正 药理和免疫学操作。 AIM 3将整合目标1和2的测量值 并基于测得的微血管构建氧对流和扩散的数值模型 形态，反应性，灌注和氧合。该模型将关联结构和功能 对组织O2供需不匹配的微血管变化，量化贡献并预测 小动脉和毛细管室，以支持组织氧合，以下o2供需 不匹配的发展。因此，该模型将阐明所有其他SVD（例如高血压，淀粉样蛋白）。共， 该建议旨在填补我们对微血管功能障碍机制的理解的重大空白 在卡达西尔，并将告知进行性神经退行性和认知的血管机制 SVD以及阿尔茨海默氏病和相关痴呆症的更常见形式的损害。