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: 10251997
• 负责人: Cleide Angolano
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251997
• 关键词: ALS patients; Acute; Address; Adverse effects; Affect; Alzheimer' s disease brain; Anti-Inflammatory Agents; Antiinflammatory Effect; Astrocytes; Attenuated; Biological; 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.

项目摘要： 血脑屏障（BBB）是一种关键的保护结构，紧紧控制生物制剂能够通过 从血液流到脑实质中，不包括毒素，但也阻止了几乎所有的 神经治疗学。专注超声（FUS）是一项新兴技术，可实现非 - BBB的侵入性和受控开放，用于交付否则将无法到达大脑的治疗剂。 使用保守的协议，如今在临床试验中进行了FUS-BBB的打开程序 成功地治疗了几种神经疾病。扩展到更广泛的临床应用 将需要将治疗参数推入与次要有关的安全问题的政权 BBB破坏的影响尚未完全理解。这些担忧包括炎症和 免疫反应，最近由我们的小组证明，是脑血流调节的改变。在这个 我们旨在了解FUS-BBB开放，神经炎症和改变的关系之间的关系 大脑血流调节，因此可以将FUS-BBB开口领域安全地向前移动到新的 申请。我们将使用最先进的光学成像技术直接测量神经元，星形细胞， FUS-BBB开口后神经血管反应的血流成分。标记 成像后立即收集的脑样本中，将评估炎症反应。数据将是 在多种强度，时间点和药物作用上获得的收购，以阐明关键机制 将FUS-BBB开口，神经炎症和神经血管反应的抑制。在目标1中，我们将 专注于FUS-BBB开口后神经元和星形胶质细胞活性的作用，以及如何变化 信号传导会影响神经血管反应的血液流量成分。在AIM 2中，我们将定义 急性神经炎症标记与神经血管反应的衰减之间的关系， 包括在FUS-BBB开口时给予的抗炎药的作用。在目标3中，我们将 研究重复的FUS-BBB开放对这些基本过程的影响，包括测试 假设预先调节炎症过程将允许随后实现BBB开口 带有柔和的响应。该项目将提供有关有关之间关系的重要新知识 FUS-BBB开口，炎症反应和神经血管反应的衰减。获得这个 知识对于将FUS-BBB开放领域安全地推向新的临床应用至关重要。