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

这个教师早期职业发展计划（CAREER）项目将为以下人员的创新治疗创造新的理解 神经变性疾病（即，阿尔茨海默氏症和帕金森氏症），促进科学进步和促进国民健康。由神经元的逐渐丧失引起的神经退行性疾病对美国的老龄化人口造成了毁灭性的损失。磁驱动可生物降解的超小纳米颗粒的最新进展为转型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，将生物技术带入精准医学和组织工程的新时代。然而，迄今为止，神经科学家主要集中在相关的生物学现象，很少关注纳米颗粒运输的微血管动力学，从而限制了临床实践的转化。本研究建立的微血管动力学模型将能够量化神经元再生过程。这对于克服固有的试错方法和接近临床成功至关重要。此外，该项目的教育和外展活动将提高人们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，包括女性和大长岛的第一代大学生。该CAREER项目的研究目标是采用分析微扰和连续方法来分析生物现象，以获得对大脑微环境中超小纳米颗粒运输的微血管动力学的丰富预测见解。该研究计划首先创建两个动态模型：一个将捕获微血管内超小纳米颗粒的磁传输行为;另一个将描述脑微血管网络内的细胞骨架动力学。结合起来，将建立纳米颗粒运输的微血管动力学模型，以识别通过在纳米颗粒上施加预定义的磁场来引导靶向选择性磁刺激以产生可靠和稳定的治疗工具所需的参数。这是第一次，与生长神经元相关的细胞骨架动力学将通过扰动在具有缓慢漂移的最小位置的势阱中扩散的纳米颗粒来解析建模。重要的是，该模型将被构建为跟踪数千个神经元的个体生长行为，并进行高通量/低成本的灵敏度分析，以确定复杂大脑微环境中的关键参数。此外，结合电力电子学的最新进展，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中神经元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价值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.