Understanding the relationships between FUS-BBB opening, neuroinflammation and the neurovascular response

了解 FUS-BBB 打开、神经炎症和神经血管反应之间的关系

• 批准号: 10458700
• 负责人: Nicholas E. Todd
• 金额: $ 21.89万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458700
• 关键词: ALS patients; Acute; Address; Adverse effects; Affect; Alzheimer' s disease brain; Anti-Inflammatory Agents; Antiinflammatory Effect; Astrocytes; Attenuated; Biological Products; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood flow; Brain; Brain Neoplasms; Calcium Signaling; Cerebrovascular Circulation; Clinic; Clinical; Clinical Trials; Data; Disease; Dose; Drug Delivery Systems; Emerging Technologies; Evoked Potentials; Focused Ultrasound; Foundations; Goals; Hour; Image; Imaging Techniques; Immune response; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Link; Measures; Mediating; Neuraxis; Neuroglia; Neurologic; Neurons; Pharmaceutical Preparations; Procedures; Process; Protocols documentation; Regulation; Research; Rodent; Role; Safety; Sampling; Secondary to; Signal Transduction; Sterility; Stimulus; Stream; Structure; Technology; Testing; Therapeutic; Time; Work; attenuation; base; blood-brain barrier disruption; blood-brain barrier permeabilization; brain health; brain parenchyma; clinical application; driving safety; imaging modality; inflammatory marker; nervous system disorder; neuroinflammation; neurovascular; neurovascular coupling; optical imaging; pre-clinical; preconditioning; response; response biomarker; tool

Project Summary: The blood-brain barrier (BBB) is a critical protective structure that tightly controls which biologics are able to pass from the blood stream into the brain parenchyma, excluding toxins but also preventing the delivery of almost all neurotherapeutics. Focused ultrasound (FUS) is an emerging technology that allows the possibility of non- invasive and controlled opening of the BBB for delivery of therapeutics that would not otherwise reach the brain. Using conservative protocols, FUS-BBB opening procedures are being done today in clinical trials, safely and successfully, for treatment of several neurological diseases. Expansion to a wider range of clinical applications will require treatment parameters to be pushed into a regime where the safety concerns related to secondary effects of BBB disruption are not fully understood. These concerns include the initiation of inflammatory and immune responses and, recently demonstrated by our group, alteration of cerebral blood flow regulation. In this project we aim to understand the relationships between FUS-BBB opening, neuroinflammation, and alteration of cerebral blood flow regulation so that the field of FUS-BBB opening can be moved forward safely into new applications. We will use state of the art optical imaging techniques to directly measure the neuronal, astrocytic, and blood flow components of the neurovascular response following FUS-BBB opening. Markers of the inflammatory response will be assessed in brain samples collected immediately after imaging. The data will be acquired over a range of intensities, time points, and drug effects in order to elucidate the key mechanisms that link FUS-BBB opening, neuroinflammation, and the suppression of the neurovascular response. In Aim 1 we will focus on the role of neuronal and astrocytic activity following FUS-BBB opening and how changes in their signaling can affect the blood flow component of the neurovascular response. In Aim 2 we will define the relationships between markers of acute neuroinflammation and the attenuation of the neurovascular response, including the effects of an anti-inflammatory drug given at the time of FUS-BBB opening. In Aim 3 we will investigate the effects of repeated FUS-BBB opening on these fundamental processes, including testing the hypothesis that pre-conditioning the inflammatory process will allow subsequent BBB openings to be achieved with a muted response. This project will deliver significant new knowledge regarding the relationship between FUS-BBB opening, the inflammatory response, and attenuation of the neurovascular response. Gaining this knowledge is critical for safely driving the field of FUS-BBB opening into new clinical applications.

项目概要： 血脑屏障 (BBB) 是一个重要的保护结构，严格控制生物制剂的通过 从血流进入脑实质，排除毒素，但也阻止几乎所有物质的输送 神经治疗学。聚焦超声 (FUS) 是一项新兴技术，可实现非 侵入性和受控地打开血脑屏障，以输送原本无法到达大脑的治疗药物。 使用保守的方案，FUS-BBB 开放程序目前正在临床试验中进行，安全且可靠 并成功治疗多种神经系统疾病。扩展到更广泛的临床应用 将需要将治疗参数纳入一个制度，其中安全问题涉及二次 BBB 破坏的影响尚未完全了解。这些问题包括引发炎症和 免疫反应，以及我们小组最近证明的脑血流调节的改变。在这个 我们的项目旨在了解 FUS-BBB 开放、神经炎症和神经功能改变之间的关系 脑血流调节使FUS-BBB开放领域能够安全地迈向新的领域 应用程序。我们将使用最先进的光学成像技术来直接测量神经元、星形细胞、 FUS-BBB 打开后神经血管反应的血流成分。的标记 将在成像后立即收集的脑样本中评估炎症反应。数据将是 在一系列强度、时间点和药物作用下获得的结果，以阐明关键机制 将 FUS-BBB 开放、神经炎症和神经血管反应抑制联系起来。在目标 1 中，我们将 重点关注 FUS-BBB 打开后神经元和星形胶质细胞活动的作用以及它们的变化 信号传导可以影响神经血管反应的血流成分。在目标 2 中，我们将定义 急性神经炎症标志物与神经血管反应减弱之间的关系， 包括 FUS-BBB 打开时给予的抗炎药物的作用。在目标 3 中，我们将 研究重复 FUS-BBB 打开对这些基本过程的影响，包括测试 假设预处理炎症过程将允许随后实现血脑屏障开放 沉默的回应。该项目将提供有关之间关系的重要新知识 FUS-BBB 打开、炎症反应和神经血管反应减弱。获得这个 知识对于安全推动 FUS-BBB 领域开放新的临床应用至关重要。