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完成向神经元提供氧气和营养的复杂任务，同时保护神经元免受有害分子的伤害。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。这些细胞对微尺度机械振动的反应是一个谜。当音调太高而听不见的声波通过组织传播时，就会发生这种振动。另一种产生微尺度振动的方法是短暂的激光脉冲。这项研究的目标是开发一种新的技术，创造受控的微尺度振动，同时在显微镜下可视化效果。本研究将使用眼后部的神经元层（视网膜）。这些实验将首次深入了解细胞如何对机械改变做出反应，并将为新的干预类别打开大门。预期细胞区分这些微尺度机械振动的音高和强度，并相应地测量它们的响应。在正常的衰老过程中或在疾病中，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。受控的微尺度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驱逐和去除这些有害分子的新可能性。首席研究员将与更广泛社区的学生和教育工作者合作，分享正在开发的新技术。一个目标将是吸引，招收和培训残疾人，妇女和少数民族在这一研究领域的个人。血视网膜屏障（BRB）选择性地调节到达神经元的分子的渗透性。对于BRB的暂时和非损伤性打开存在未满足的科学和医学需求。该项目的目标是A）开发一种新技术，在活体显微镜下向视网膜提供微尺度机械振动，B）可视化BR B中这些微尺度振动的效果，以及C）计算模拟分子通过BR B的过程。预期结果将是图像引导的BRB声学和/或光声改变。该项目团队的方法将体内动物实验与计算机模拟相结合。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技术，使用定制开发的硬件通过图像引导方法实时研究由此产生的动态过程。将根据质量平衡方程建立计算模型。在啮齿动物中，将通过血管造影图像的定量分析测量BRB渗透性。体内实验的结果将完善计算模型。一个同伴项目正在由德国联邦教育和研究部（BMBF）资助。该项目由以下NSF项目共同资助：残疾和康复工程以及计算神经科学合作研究。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。