CAREER: Deconstructing Neurovascular Mechanobiology

相对于身体其他部位的血管，大脑中的血管具有特殊的功能，这使得它们在允许哪些物质在血液和大脑之间转移方面非常有选择性。这种功能通常被称为血脑屏障（BBB），并可能在各种脑部疾病中受损，但这种变化的原因通常不清楚。本学院早期职业发展计划（Career）奖的目标是调查血管细胞外基质硬度变化是血脑屏障功能障碍的原因之一的假设。这项研究将通过直接对从小鼠和人类脑组织中解剖的血管进行测量，以及通过从人类干细胞中建立血管模型来精确控制基质刚度和其他参数来完成。这些结果将为了解衰老或疾病引起的脑血管生理学变化进展的基本过程提供关键见解。结合这项研究计划，将拟订和传播新的教育和外联活动。与当地艺术家和高中生合作，他们将在PI？在美国实验室，将开发一系列教育材料，解释干细胞如何用于理解和治疗疾病。这些材料将通过纳什维尔科学推广中心、经济困难学生的课后俱乐部和一年一度的神经科学活动传播，从而促进当地社区的学习和参与。该奖项的总体研究目标是了解血脑屏障的力学生物学，特别是脑血管力学与血脑屏障功能的相互作用。这将通过两个主要的研究目标来完成。第一个目标是从根本上描述神经血管组织刚度如何影响原位（天然组织）和体外（工程组织）的血脑屏障功能。该项目的原位部分将描述神经血管僵硬、血脑屏障渗漏和细胞外基质重塑作为年龄和疾病的功能，使用小鼠和人类脑组织样本。这项工作的体外部分将利用能模拟这种结构的诱导多能干细胞来开发血脑屏障模拟物。然后，这些模拟将用于直接检查底物刚度对血脑屏障功能的影响。第二个目标是阐明在2D和3D培养中调节神经血管硬化的生物物理机制，特别是机械触发和分子信号。重点将放在构成血脑屏障的各种细胞的自主信号和串扰信号上。更全面地了解血脑屏障——特别是在衰老和其他病理过程中发生的血管硬度变化如何影响其功能——是理解脑血管生理学和物质如何运输（或阻止运输）到脑组织的关键领域。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。

Relative to blood vessels in the rest of the body, the blood vessels in the brain have specialized functions that make them very selective with respect to what substances they permit to transfer between the bloodstream and the brain. This function is commonly referred to as the blood-brain barrier (BBB) and may become compromised in various brain diseases, but the reason for this change is often unclear. The goal of this Faculty Early Career Development Program (CAREER) award is to investigate the hypothesis that changes in the stiffness of the extracellular matrix of blood vessels are one of the causes of dysfunction of the blood-brain barrier. This research will be accomplished by conducting measurements directly on blood vessels dissected from mouse and human brain tissue as well as by building blood vessel models from human stem cells through which the matrix stiffness and other parameters can be precisely controlled. These results will provide key insight into fundamental processes related to the progression of changes in brain vascular physiology due to aging or disease. In conjunction with this research plan, new educational and outreach activities will be developed and disseminated. In collaboration with a local artist and high school students who will perform research in the PI?s lab, a series of educational materials will be developed to explain how stem cells can be used for understanding and treating diseases. These materials will be disseminated at a Nashville science outreach center, through after-school clubs for economically disadvantaged students, and a yearly neuroscience event, thus promoting learning and engagement in the local community. The overall research goal of this award is to understand the mechanobiology of the blood-brain barrier, specifically related to the interaction of the cerebrovascular mechanics with BBB function. This will be accomplished through two primary research objectives. The first objective is to fundamentally characterize how neurovascular tissue stiffness influences blood-brain barrier function in situ (in natural tissue) and in vitro (in engineered tissue). The in situ portion of the project will characterize the neurovascular stiffness, blood-brain barrier leakage, and extracellular matrix remodeling as a function of age and disease using mouse and human brain tissue samples. The in vitro portion of the work will develop blood-brain barrier mimics using induced pluripotent stem cells that can model this structure. These mimics will then be used to directly examine the effect of substrate stiffness on blood-brain barrier function. The second objective is to elucidate the biophysical mechanisms, specifically the mechanical triggers and the molecular signals, that regulate neurovascular stiffening in 2D and 3D culture. The focus will be on both autonomous and cross-talk signaling for the various cells that make up the blood-brain barrier. Understanding more fully the blood-brain barrier -- and in particular how changes in vascular stiffness that occur during aging and other pathologies may impact its function -- is a key area for understanding cerebrovascular physiology and how materials can be transported (or prevented from being transported) to the brain tissue.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.