Two-Photon Microscopy of Oxygen Consumption in the Brain

大脑耗氧量的双光子显微镜

• 批准号: 9103239
• 负责人: Sava Sakadzic
• 金额: $ 45.48万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103239
• 关键词: Affect; Algorithms; Alzheimer' s Disease; Anesthesia procedures; Animal Model; Anoxia; Brain; Brain Diseases; Brain Injuries; Cerebral Ischemia; Cerebrum; Chronic; Clinical; Complex; Consumption; Dementia; Development; Disease; Dyes; Event; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Growth; Hypercapnia; Hypertension; Hypoxia; Image; Imaging Device; Imaging Techniques; Investigation; Ischemia; Ischemic Penumbra; Lead; Lesion; Maps; Measurement; Measures; Metabolic Activation; Metabolism; Methods; Microcirculation; Microscopic; Microscopy; Microvascular Dysfunction; Modeling; Nerve Degeneration; Neurons; Optical Coherence Tomography; Oxygen; Oxygen Consumption; Partial Pressure; Physiological; Pilot Projects; Positron-Emission Tomography; Protocols documentation; Recurrence; Resolution; Rest; Rodent; Scanning; Seizures; Speed; Stroke; Structure; Study Section; Techniques; Technology; Testing; Time; Tissues; arteriole; base; brain tissue; cerebral hypoperfusion; cerebral oxygenation; chronic stroke; imaging biomarker; imaging modality; improved; in vivo; innovation; metabolic rate; microPET; microscopic imaging; new technology; novel; phosphorescence; pressure; progressive neurodegeneration; public health relevance; spatiotemporal; temporal measurement; tissue oxygenation; tool; treatment strategy; two-photon

 DESCRIPTION (provided by applicant): PROJECT ABSTRACT A critical gap remains in our understanding of oxygen metabolism, delivery, and reserve, both at rest and during metabolic activation states in healthy and diseased brain. Available imaging techniques lack spatial and temporal resolution to assess distribution of cerebral tissue oxygenation (PO2) and O2 consumption (CMRO2) with adequate level of detail, and to unravel their dynamic changes within microvascular domains. We propose to develop and validate a new microscopic imaging method of resting state CMRO2 in small animal models, and advance it to enable rapid high spatial resolution imaging of CMRO2 and PO2. The new technology will enable regional estimation of CMRO2 at a rate of ~1 Hz together with acquisition of detailed tissue PO2 maps, which is essential for advancing our understanding of O2 delivery and consumption in the brain. In Aim1 we will develop and validate high-resolution resting state CMRO2 imaging method in small rodents based on two- photon PO2 microscopy. This new method will measure resting state regional CMRO2 based on tissue PO2 profiles around cortical penetrating arterioles. In Aim 2 we will advance new CMRO2 imaging method by improving a multifocal, frequency modulated, two-photon phosphorescence lifetime imaging to allow practical rapid PO2 imaging in optically scattering brain tissue, and to improve the speed of CMRO2 measurements up to 100-fold (approaching 1 Hz). In Aim 3 we will quantify regional CMRO2 during physiological and pathological perturbations. We will test the hypothesis that "transient physiological or pathological neuronal activation in a brain affected by ischemia leads to a mismatch between O2 metabolism and supply and hypoxia within microvascular domains" - a mechanism that may underlie lesion growth in stroke and other brain injury states as well as progressive neurodegeneration observed in microvasculopathies. This technology will have broad utility in quantifying metabolism and oxygenation in cerebral microvascular domains in animal models of brain disorders that will dramatically advance our understanding of pathophysiology and lead to novel treatment strategies in important clinical problems such as chronic cerebral hypoperfusion, stroke, small vessel disease, and AD dementia.

 描述(由申请人提供)： 项目摘要在健康和疾病大脑中，无论是在静息状态还是在代谢激活状态，我们对氧代谢、输送和储备的理解仍然存在一个关键的差距。现有的成像技术缺乏足够详细的空间和时间分辨率来评估脑组织氧合(PO2)和氧耗(CMRO2)的分布，并揭示其在微血管区域内的动态变化。我们建议开发和验证一种新的小动物模型静息状态CMRO2的显微成像方法，并将其改进为能够对CMRO2和PO2进行快速高空间分辨率成像。这项新技术将使我们能够以~1赫兹的频率对CMRO2进行区域性估计，并获得详细的组织PO2图，这对于促进我们对O2在大脑中的输送和消耗的理解是必不可少的。在Aim1中，我们将开发和验证基于双光子PO2显微镜的小鼠静息状态高分辨率CMRO2成像方法。这一新方法将基于皮质穿透小动脉周围组织的PO2分布来测量静息状态下的区域CMRO2。在目标2中，我们将通过改进多焦点、调频、双光子磷光寿命成像来改进新的CMRO2成像方法，以允许在光学散射的脑组织中进行实用的快速PO2成像，并将CMRO2的测量速度提高到100倍(接近1赫兹)。在目标3中，我们将量化生理和病理扰动期间的局部CMRO2。我们将检验这一假设：“大脑中短暂的生理性或病理性神经元激活受 脑缺血导致氧气代谢和供应不匹配以及微血管内缺氧“--这可能是中风和其他脑损伤状态下的病变生长以及微血管病变中观察到的进行性神经变性的基础机制。这项技术将在量化脑部疾病动物模型的脑微血管区域的代谢和氧合方面具有广泛的实用价值，将极大地提高我们对病理生理学的理解，并为慢性脑灌流不足、中风、小血管疾病和AD痴呆等重要临床问题提供新的治疗策略。