CRCNS US-German Research Proposal: Computational modeling and real-time visualization of microscale-forces-induced neurovascular unit permeability

CRCNS 美德研究提案：微尺度力诱导的神经血管单元渗透性的计算建模和实时可视化

• 批准号: 2207804
• 负责人: Ali Hafezi-Moghadam
• 金额: $ 46.28万
• 依托单位: Brigham & Women's Hospital Inc
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2207804&HistoricalAwards=false
• 关键词: CRCNS; US; German; Research; Proposal

The blood vessels in the central nervous system fulfill the complicated task of providing oxygen and nutrients to the neurons, while at the same time protecting the neurons from harmful molecules. This is accomplished through tight opposition and closure of the cells that cover the inner surfaces of these vessels. How these cells respond to microscale mechanical vibrations is a mystery. Such vibrations occur when sound waves that are too high-pitched to be audible propagate through tissues. Another way to generate microscale vibrations is a brief laser pulse. The goal of this research is to develop a novel technology that creates controlled microscale vibrations, while at the same time microscopically visualizing the effect. The neuronal layer in the back of the eye, the retina, will be used for this study. These experiments will provide for the first time insights into how cells react to mechanical alterations and will open the door to a new category of interventions. It is expected that cells distinguish the pitch and intensity of these microscale mechanical vibrations and gauge their responses accordingly. During normal aging or in diseases, such as Alzheimer’s disease, aberrant molecules accumulate around neurons and impede their normal functioning. Controlled microscale mechanical vibrations bring about new possibilities for dislodging and removing these deleterious molecules before neurons are harmed and the individuals’ cognitive or visual functions decline. The principal investigator will engage with students and educators in the broader community to share the novel technologies under development herein. A goal will be to attract, enroll, and train individuals with disabilities, women, and minorities in this area of research. The Blood-Retina-Barrier (BRB) selectively regulates the permeability of molecules that reach the neurons. There is an unmet scientific and medical need for a temporal and non-injurious opening of the BRB. The goals of this project are A) development of a novel technology to deliver microscale mechanical vibrations to the retina under live microscopy, B) to visualize the effect of these microscale vibrations in the BRB, and C) to computationally model the process of the molecular passage through the BRB. The expected outcome will be image-guided acoustic and/or photo-acoustic alterations of the BRB. The project team's approach combines in vivo animal experiments with computational modeling in silico. To modulate BRB’s permeability, the project team will implement a recently developed new laser-based photo-acoustic and pure acoustic technologies to study the resulting dynamic processes in real-time with an image-guided approach using custom-developed hardware. A computational model will be developed based on mass balance equations. In rodents, BRB permeability will be measured through quantitative analysis of angiographic images. The results of the in vivo experiments will refine the computational modeling.A companion project is being funded by the Federal Ministry of Education and Research, Germany (BMBF). This project is jointly funded by the following NSF programs: Disability and Rehabilitation Engineering and Collaborative Research in Computational Neuroscience.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

中枢神经系统中的血管履行了为神经元提供氧气和养分的编译任务，同时保护神经元免受有害分子的影响。这是通过覆盖这些血管内表面的细胞的紧密对立和闭合来实现的。这些细胞如何响应微观机械振动是一个神秘的。当声波太高而无法听到通过组织传播时，就会发生这种振动。产生微观振动的另一种方法是简短的激光脉冲。这项研究的目的是开发一种新的技术，该技术产生受控的微观振动，同时显微镜地可视化效果。眼后视网膜的神经元层将用于本研究。这些实验将首次提供有关细胞如何对机械改变的反应的见解，并将为新的干预措施打开门。预计细胞会区分这些显微镜机械振动的音高和强度，并相应地评估它们的响应。在正常衰老或疾病中，例如阿尔茨海默氏病，异常分子在神经元周围积聚并阻碍其正常功能。受控的显微镜机械振动带来了在神经元受到伤害和个体的认知或视觉功能下降之前脱落和去除这些微妙分子的新可能性。首席研究人员将与更广泛社区的学生和教育者互动，以共享此处开发的新技术。一个目标是在这一研究领域吸引，入学和培训残疾人，妇女和少数民族的人。血液 - 逆转录器（BRB）有选择地调节到达神经元的分子的渗透性。该项目的目标是未满足的科学和医疗需求，是a）开发一种新技术，以在实时显微镜下向视网膜传递显微镜机械振动，b）可视化BRB中这些显微镜振动的效果，c）计算在计算上模拟通过BRB的分子传递的过程。预期的结果将是图像引导的BRB的声学和/或光声变化。项目团队的方法将体内动物实验与计算机模型相结合。为了调节BRB的渗透性，项目团队将实施最近开发的新的基于激光的光声和纯声学技术，以使用自定义开发硬件的图像引导的方法实时研究产生的动态过程。计算模型将基于质量平衡方程开发。在啮齿动物中，将通过对血管造影图像的定量分析来测量BRB渗透率。体内实验的结果将完善计算建模。一个伴侣项目由德国联邦教育和研究部（BMBF）资助。该项目由以下NSF计划共同资助：计算神经科学领域的残疾和康复工程和协作研究。该奖项反映了NSF的法定任务，并被认为是通过基金会的智力优点和更广泛影响的审查标准通过评估来通过评估来支持的。