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: 10646249
• 负责人: Song Hu
• 金额: $ 62.38万
• 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/10646249
• 关键词: Acoustics; Acute; Adverse effects; 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; Knockout Mice; Life Expectancy; Light; Maps; Medical Care Costs; Metabolic; Metabolism; Microscopic; Microscopy; Modality; Molecular; Motor; Mus; Neurons; Optics; Oxygen; Patients; Penetration; Performance; Persons; Process; Productivity; Property; Recovery; Recovery of Function; Research; Resolution; Sensory; Silicon; Stroke; Survival Rate; Survivors; Synaptic plasticity; System; Techniques; Testing; Transducers; Ultrasonics; United States; acute stroke; angiogenesis; awake; brain repair; burden of illness; cerebrovascular; cognitive function; cost; design; disability; genetic manipulation; hemodynamics; improved; improved outcome; in vivo; insight; intravital imaging; light transmission; microscopic imaging; model organism; neural; neural circuit; neural repair; neuronal circuitry; neurovascular; neurovascular coupling; new therapeutic target; post stroke; prototype; repaired; restoration; sensor; serial imaging; spatiotemporal; stroke recovery; stroke therapy; technology development; transmission process; two photon microscopy; two-photon; ultrasound

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.

项目概要 美国每年有超过 800,000 人患有中风。尽管绝大多数都幸存下来 急性事件中，超过一半的幸存者会出现运动、感觉或认知功能中度至重度损伤。 因此，中风仍然是导致长期残疾的主要原因，每年造成的损失超过 340 亿美元。 美国的直接医疗费用和间接费用（生产力损失）。面对这个巨大的疾病 负担，但几乎没有什么疗法可以改善中风康复。大脑具有一定的内在修复能力，但是 我们对根本机制的了解仍然非常有限。最近的研究表明，成功的 中风损伤的恢复需要神经血管重塑来重组受损的大脑网络。的确， 电路修复和由此产生的重新映射对于中风恢复至关重要。此外，脑血管重构 在中风后的动物和患者中观察到脑氧代谢的变化，并且与 并取得更好的成果。可能需要神经修复和脑血管重塑的紧密协调 满足大脑修复的能量需求。然而，神经血管修复的时空协调和 中风后随之而来的氧代谢变化仍不完全清楚。我们寻求答案 通过开发一种集成 2 光子的新型双模态活体成像技术来解决这些重要问题 荧光显微镜（TPM）和多参数光声显微镜（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效和综合成像。为此，我们 开发了原型 TPM-PAM 系统和具有双重透明度（即光和 超声波），使用寿命长，并且与清醒脑成像兼容。建立在坚实的科学基础之上， 拟议项目将重点开发用于纵向成像的高灵敏度 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 神经元活动、血流和血氧供应之间耦合的成像，在单神经元单 清醒小鼠大脑中的毛细血管水平。拟议的研究有三个具体目标：（1）开发一种光学 用于集成 TPM 和 PAM 的透明声敏微谐振器，具有高灵敏度，(2) 开发并验证基于微谐振器的 TPM-PAM，用于 GCaMP 小鼠的神经血管成像，以及 (3) 确定功能性血管修复和神经元回路修复之间的时空关系 中风。通过 TPM-PAM 的开发和应用加深我们对中风修复的理解 揭示有希望的新治疗靶点，以促进功能恢复。