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

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侵害。这是通过紧密的对立和封闭覆盖这些血管内表面的细胞来实现的。这些细胞对微观机械振动的反应是一个谜。当声波在组织中传播时，由于音调太高而听不见，就会产生这种振动。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技术，可以产生可控的微尺度振动，同时在微观上可视化效果。眼睛后部的神经元层，即视网膜，将被用于这项研究。这些实验将首次提供对细胞如何对机械变化作出反应的见解，并将为一种新的干预手段打开大门。预计细胞可以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反应。在正常衰老或阿尔茨海默病等疾病中，异常分子会聚集在神经元周围，阻碍它们的正常功能。受控制的微尺度机械振动为在神经元受损和个体认知或视觉功能下降之前移除这些有害分子带来了新的可能性。首席研究员将与学生和教育工作者在更广泛的社区参与，分享在这里开发的新技术。目标将是在这一研究领域吸引、招收和培训残疾人、妇女和少数民族。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。目前尚未满足的科学和医学需求是暂时且无伤害地打开BRB。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传递微尺度机械振动，B)可视化这些微尺度振动在BRB中的影响，以及C)计算分子通过BRB的过程模型。预期结果将是BRB的图像引导声学和/或光声改变。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的渗透率，项目团队将采用最近开发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产生的动态过程。将根据质量平衡方程建立一个计算模型。在啮齿类动物中，BRB的通透性将通过血管造影图像的定量分析来测量。体内实验的结果将完善计算模型。德国联邦教育和研究部（BMBF）正在资助一个伙伴项目。本项目由以下NSF项目联合资助：残疾与康复工程和计算神经科学合作研究。该奖项反映了美国国家科学基金会的法定使命，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。

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.