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: 10615010
• 负责人: Cenk Ayata
• 金额: $ 69.32万
• 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/10615010
• 关键词: Alzheimer' s disease related dementia; Amyloid; Animal Genetics; Animal Model; Antibodies; Area; Arterial Disorder; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Diseases; Brain region; CADASIL; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrum; 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; 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; Publishing; Research; Resolution; Rest; Signal Transduction; Smooth Muscle Myocytes; Stroke; Structural defect; Subcortical Infarctions; Subcortical Leukoencephalopathy; TIMP3 gene; Testing; Time; Tissues; Transgenic Mice; Transgenic Model; Trees; Vascular Smooth Muscle; Visualization; Work; age related; arteriole; autosome; awake; 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; pharmacologic; 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.

项目总结/摘要 尽管进行了大量的研究，但我们对结构和功能的变化 脑小血管疾病（SVD）与组织氧合有关，无论这是否会导致组织 缺氧（O2供需不匹配），以及不同的微血管段如何导致这种不匹配 在不同的大脑区域。利用我们先进的光学成像工具，可检测绝对pO 2、血流、Ca 2 + 信号传导和微血管形态，以及临床相关的CADASIL小鼠模型，我们建议 第一次检查微血管功能障碍和O2供需不匹配之间的因果关系。 CADASIL（大脑常染色体显性遗传性动脉病伴皮质下白质脑病）是一种 最常见的单基因遗传形式的SVD导致痴呆，由Notch 3突变引起。 CADASIL的转基因模型概括了该疾病的许多临床和组织病理学特征， 包括SVD的早期体征，如受损的CBF和功能性充血反应，以及功能性和 小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pO 2、O2代谢率（CMRO 2）、CBF和毛细血管红 血细胞流量和微血管形态，在休息和功能性脑激活期间，在灰色和 白色物质，纵向数月，在未麻醉的CADASIL转基因小鼠。目标1将测试 CADASIL导致年龄依赖性O2供需不匹配，表现为静息时胰岛组织缺氧， 在功能激活期间。结合双光子显微镜和光学相干断层扫描（OCT），我们 将测试CADASIL是否会导致毛细血管红细胞流量异常和毛细血管通过时间增加 异质性导致O2供需不匹配，甚至在绝对CBF减少之前 manifest.最后，我们将研究氧气供需不匹配是否可以通过遗传， 药理学和免疫学操作。目标2将测试CADASIL是否会导致Ca 2 + 血管平滑肌和周细胞的失调以及它是否可以通过遗传， 药理学和免疫学操作。目标3将整合目标1和目标2的测量结果 并根据微血管测量结果建立了氧气对流扩散的数值模型， 形态学、反应性、灌注和氧合。该模型将结构和功能 微血管变化对组织O2供需不匹配的影响，量化其贡献并预测 小动脉和毛细血管隔室，以支持组织氧合，低于该氧供需 失配发展。因此，该模型将揭示所有其他SVD（例如高血压，淀粉样蛋白）。总的来说， 该建议旨在填补我们对微血管功能障碍机制理解的重大空白 在CADASIL中，并将告知进行性神经变性和认知功能障碍的血管机制。 在更常见的SVD形式以及阿尔茨海默病和相关痴呆症中的损伤。