Integrating TPM and PAM to examine the metabolic underpinning of neurovascular repair after stroke

整合 TPM 和 PAM 检查中风后神经血管修复的代谢基础

• 批准号: 10317720
• 负责人: Song Hu
• 金额: $ 64.97万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317720
• 关键词: Acoustics; Acute; Adverse effects; Animal Model; Animals; Behavioral; Benchmarking; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Injuries; Brain imaging; Cephalic; Cerebrum; Collection; Computer software; Coupling; Data; Detection; Development; Event; Facilities and Administrative Costs; Financial Hardship; Fluorescence; Fluorescence Microscopy; Image; Imaging Techniques; Impairment; Individual; Infarction; Injury; Ischemic Stroke; Knock-out; Life; Light; Medical Care Costs; Metabolic; Metabolism; Microscopic; Microscopy; Modality; Molecular; Molecular Genetics; Motor; Mus; Neurons; Optics; Oxygen; Patients; Penetration; Performance; Process; Productivity; Property; Recovery; Recovery of Function; Research; Resolution; Sensory; Silicon; Stroke; Survival Rate; Survivors; Synaptic plasticity; System; Techniques; Testing; Time; Transducers; Ultrasonics; Ultrasonography; United States; acute stroke; angiogenesis; awake; base; brain repair; burden of illness; cerebrovascular; cognitive function; cost; design; disability; genetic manipulation; hemodynamics; improved; improved outcome; in vivo evaluation; insight; intravital imaging; light transmission; microscopic imaging; neural circuit; neuronal circuitry; neurovascular; neurovascular coupling; new therapeutic target; post stroke; prototype; relating to nervous system; repaired; restoration; sensor; serial imaging; spatiotemporal; stroke recovery; stroke therapy; technology development; transmission process; two photon microscopy; two-photon

PROJECT SUMMARY Each year, over 800,000 people in the United States suffer from a stroke. Although the vast majority survive the acute event, over half of survivors suffer moderate to severe impairment in motor, sensory, or cognitive function. As a consequence, stroke remains the leading cause of long-term disability, costing over $34 billion annually in direct medical costs and indirect costs (lost productivity) in the United States. In the face of this enormous disease burden, there are few therapies to improve stroke recovery. The brain has some intrinsic capacity for repair, but our understanding of the underlying mechanisms remains very limited. Recent studies suggest that a successful recovery from stroke injury requires neurovascular remodeling to reorganize the damaged brain network. Indeed, circuit repair and the resultant remapping is essential for stroke recovery. Moreover, cerebrovascular remodeling and changes in cerebral oxygen metabolism are observed in animals and patients after stroke and are associated with improved outcomes. Tight coordination of neural repair and cerebrovascular remodeling is likely required to meet energy requirements of brain repair. However, the spatiotemporal coordination of neurovascular repair and the attendant changes in oxygen metabolism after stroke remain incompletely understood. We seek to answer these important questions by developing a new dual-modal intravital imaging technique that integrates 2-photon fluorescence microscopy (TPM) and multi-parametric photoacoustic microscopy (PAM) for high-resolution, time- lapse and comprehensive imaging of neurovascular repair and metabolic changes after stroke. To this end, we have developed a prototype TPM-PAM system and a new cranial window with dual transparency (i.e., light and ultrasound), long lifetime, and compatibility for awake-brain imaging. Building on the strong scientific basis, this proposed project will focus on the development of a high-sensitivity TPM-PAM system for longitudinal imaging of the spatiotemporal interplay of post-stroke neural repair and cerebrovascular remodeling, as well as dynamic imaging of the coupling between neuronal activity, blood flow, and blood oxygen supply, at single-neuron single- capillary level in the awake mouse brain. The proposed research has three specific aims: (1) develop an optically transparent and acoustically sensitive microresonator for integration of TPM and PAM with high sensitivity, (2) develop and validate the microresonator-based TPM-PAM for neurovascular imaging in GCaMP mice, and (3) determine the spatiotemporal relationship between functional vascular repair and neuronal circuit repair after stroke. Advancing our understanding of stroke repair through the development and application of TPM-PAM may reveal promising new therapeutic targets to enhance functional recovery.

项目摘要 每年，美国有超过80万人患有中风。尽管绝大多数人幸存下来 急性事件，超过一半的幸存者在运动，感觉或认知功能中遭受中等至重度损害。 结果，中风仍然是长期残疾的主要原因，每年耗资超过340亿美元 在美国，直接的医疗费用和间接成本（生产率损失）。面对这种巨大疾病 负担，几乎没有疗法可以改善中风恢复。大脑具有维修的内在能力，但是 我们对基本机制的理解仍然非常有限。最近的研究表明成功 从中风损伤中恢复需要神经血管重塑，以重组受损的大脑网络。的确， 电路维修和结果重新映射对于中风恢复至关重要。此外，脑血管重塑 并且在中风后动物和患者观察到脑氧代谢的变化，并且相关 有改善的结果。可能需要进行神经修复和脑血管重塑的紧密协调 满足大脑维修的能量需求。但是，神经血管修复的时空协调和 中风后氧代谢的氧气代谢的变化尚不完全理解。我们寻求回答 这些重要问题通过开发一种新的双模式插入成像技术，该技术整合了2-Photon 荧光显微镜（TPM）和多参数光声学显微镜（PAM），用于高分辨率，时间 - 中风后神经血管修复和代谢变化的失误和全面成像。为此，我们 已经开发了一个原型TPM-PAM系统和具有双透明度的新颅窗（即光和 超声波），寿命长和兼容性，用于清醒 - 脑成像。以强烈的科学为基础，这 拟议的项目将着重于开发用于纵向成像的高敏性TPM-PAM系统 中风后神经修复和脑血管重塑的时空相互作用以及动态 单神经元单神经元的神经元活性，血流和血氧供应之间的耦合成像 清醒小鼠大脑中的毛细血管水平。拟议的研究具有三个特定的目的：（1）在光学上开发 透明和声学敏感的微孔子，用于以高灵敏度整合TPM和PAM，（2） 开发并验证基于微孔孔蛋白的TPM-PAM用于GCAMP小鼠的神经血管成像，（3） 确定功能性血管修复与神经元电路修复之间的时空关系 中风。通过开发和应用TPM-PAM来促进我们对中风维修的理解可能 揭示有希望的新治疗靶标，以增强功能恢复。