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

项目总结： 血脑屏障(Bbb)是一种关键的保护结构，它严格控制哪些生物物质能够通过。 从血流进入脑实质，排除毒素，但也阻止了几乎所有 神经治疗学。聚焦超声(FUS)是一种新兴的技术，它允许非 有创性地和受控地打开血脑屏障，以提供否则无法到达大脑的治疗药物。 使用保守方案，FUS-BBB开放程序今天正在临床试验中进行，安全和 成功地，用于治疗几种神经疾病。扩展到更广泛的临床应用 将要求治疗参数被推入一种与继发性疾病相关的安全担忧的方案 血脑屏障中断的影响还没有完全了解。这些关切包括引发炎症性和 免疫反应和我们小组最近证实的脑血流调节的改变。在这 我们的项目旨在了解FUS-BBB开放、神经炎症和血管紧张素转换酶改变之间的关系。 调节脑血流使FUS-BBB开放领域安全前移 申请。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， 以及FUS-BBB开放后神经血管反应的血流成分。标记物： 炎症反应将在成像后立即收集的大脑样本中进行评估。数据将是 在一系列强度、时间点和药物效应上获得，以阐明 链接FUS-BBB开放，神经炎症，和神经血管反应的抑制。在目标1中，我们将 重点关注FUS-BBB开放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 急性神经炎标志物与神经血管反应减弱的关系 包括在FUS-BBB打开时给予的抗炎药的效果。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 预调节炎症过程将允许随后的血脑屏障开放的假说 无声地回应。这个项目将提供关于两国之间关系的重要新知识 FUS-BBB开放、炎症反应和神经血管反应的减弱。获得这一点 知识对于将FUS-BBB领域安全地推向新的临床应用至关重要。

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.