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.

项目概要/摘要 尽管进行了大量研究，但我们对结构和功能如何变化甚至缺乏最基本的了解 脑部小血管疾病 (SVD) 与组织氧合有关，这是否会导致组织 缺氧（氧气供需不匹配），以及不同的微血管段如何导致这种不匹配 利用我们尖端的光学成像工具测量绝对氧分压、血流量、Ca2+。 信号传导、微血管形态以及临床相关的 CADASIL 小鼠模型，我们建议 首次研究微血管功能障碍与氧气供需不匹配之间的因果关系。 CADASIL（伴有皮质下梗塞和白质脑病的常染色体显性遗传性脑动脉病）是 最常见的 SVD 单基因遗传形式，可导致痴呆，由 Notch3 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 的早期症状，例如 CBF 受损和功能性充血反应，以及功能性和功能性充血反应。 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 pO2、O2 代谢率 (CMRO2)、CBF 和毛细血管红 休息时和功能性大脑激活期间的血细胞流量和微血管形态（灰色和灰色） 目标 1 将测试未麻醉的 CADASIL 转基因小鼠的白质，纵向观察数月。 CADASIL 导致年龄依赖性 O2 供需失配，表现为静息或胰岛组织缺氧 结合双光子显微镜和光学相干断层扫描（OCT），我们 将测试CADASIL是否导致毛细血管红细胞通量异常和毛细血管转运时间增加 即使在绝对 CBF 减少之前，异质性也会导致 O2 供需失配 最后，我们将研究氧气供需失配是否可以通过遗传、 目标 2 将测试 CADASIL 是否会导致 Ca2+。 血管平滑肌和周细胞的失调以及是否可以通过遗传、 目标 3 将整合目标 1 和目标 2 的测量结果。 并根据测量的微血管构建了氧气平流和扩散的数值模型 该模型将结构和功能联系起来。 组织 O2 供需不匹配的微血管变化，量化其贡献并预测其极限 小动脉和毛细血管室支持组织氧合，低于该值 O2 供需 因此，该模型将揭示所有其他 SVD（例如高血压、淀粉样蛋白）。 该提案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，并将揭示进行性神经退行性变和认知的血管机制 更常见形式的 SVD 以及阿尔茨海默病和相关痴呆症的损害。