CAREER: Understanding Dynamics of Ultra-small Magnetic Nanoparticles in the Brain for Neuron Regeneration Therapies

这一学院早期职业发展计划(CALEAR)项目将对神经退行性疾病(即阿尔茨海默氏症和帕金森氏症)的创新治疗方法产生新的理解，并促进科学进步和促进国民健康。神经退行性疾病是由神经元的进行性丧失引起的，对美国老龄化人口造成毁灭性的损失。磁驱动可生物降解超微纳米颗粒的最新进展为变革性的非侵入性神经元再生治疗提供了机会。这项创新技术具有巨大的潜力，可以将生物技术带入精准医学和组织工程的新时代。然而，到目前为止，神经科学家主要关注与之相关的生物现象，对纳米颗粒转运的微血管动力学很少关注，从而限制了将其转化为临床实践。通过本研究建立的微血管动力学模型将能够量化神经元的再生过程。这对于克服固有的反复试验的方法和更接近临床成功是至关重要的。此外，该项目的教育和外联活动将提高对纳米技术和生物医学的认识，并将增加STEM中历史上代表性不足的群体的参与，包括妇女和大长岛的第一代大学生。这一职业项目的研究目标是使用分析微扰和连续方法来分析生物现象，以获得对超小纳米颗粒在脑微环境中运输的微血管动力学的丰富预测性见解。这项研究计划首先创建两个动态模型：一个将捕捉超小纳米颗粒在微血管系统中的磁性传输行为；另一个将描述脑微血管网络中的细胞骨架动力学。结合起来，将建立纳米颗粒传输的微血管动力学模型，以识别需要哪些参数来指导靶向选择性磁刺激，通过在纳米颗粒上施加预先定义的磁场来产生可靠和稳定的治疗工具。第一次，与生长的神经元相关的细胞骨架动力学将通过扰动纳米颗粒在具有缓慢漂移的最小位置的势井中扩散来进行分析建模。重要的是，这个模型将被构建来跟踪数千个神经元的个体生长行为，并执行高通量/低成本的敏感性分析，以确定复杂大脑微环境中的关键参数。此外，结合电力电子领域的最新进展，该项目具有很高的潜力，有助于开发一种新的微芯片，提高研究人员研究三维细胞外基质内神经细胞生长行为的能力。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development Program (CAREER) project will create new understanding of an innovative treatment for neurodegenerative diseases (i.e., Alzheimer's and Parkinson's) and promote the progress of science and advance the national health. Neurodegenerative disease, resulting from the progressive loss of neurons, takes a devastating toll on the aging population in the U.S. Recent advances in magnetically driven biodegradable ultra-small nanoparticles offer opportunities in transformational non-invasive neuron regeneration treatments. This innovative technology holds great potential to usher biotechnology into a new era of precision medicine and tissue engineering. However, to date, neuroscientists have largely focused on the associated biological phenomena, with little attention to microvascular dynamics of nanoparticle transport, thus limiting the translation to clinical practice. The microvascular dynamic model, established from this research will be capable of quantifying the neuron regeneration process. This is essential for overcoming intrinsic trial-and-error approaches and for moving closer to clinical success. Additionally, the education and outreach activities of the project will advance awareness of nanotechnology and biomedicine, and will increase the participation of historically underrepresented groups in STEM, including women, and first-generation college students in the greater Long Island. The research objective of this CAREER project is to employ analytical perturbative and continuation approaches to analyze biological phenomena to yield a rich harvest of predictive insights into the microvascular dynamics of ultra-small nanoparticles transport in a brain microenvironment. The research plan is to first create two dynamic models: one will capture the magnetic transport behavior of ultra-small nanoparticles within a microvasculature; the other will describe cytoskeleton dynamics within brain microvascular networks. Combined, a microvascular dynamic model of nanoparticle transport will be established to discern which parameters are needed for directing target-selective magnetic stimulation to produce a reliable and steady therapeutic tool by applying a pre-defined magnetic field on the nanoparticles. For the first time, cytoskeleton dynamics associated with growing neurons will be analyticaly modeled by perturbing a nanoparticle diffusing in a potential well with a slowly drifting minimum position. Importantly, this model will be constructed to track the individual growing behaviors of thousands of neurons, and perform high-throughput/low-cost sensitivity analyses to identify the key parameters in a complex brain microenvironment. Furthermore, combined with recent advances in power electronics, this project holds a high potential for contributing to the development of a new microchip that improves researcher capacity for studying the growth behavior of the neuron cells inside a three dimensional extracellular matrix.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.