CAREER: Diagnosing the Undiagnosable: Using Enzyme Upregulation to Probe Cellular Behavior in Neuropathic Lysosomal Storage Disease

该项目的目标是开发一种使用被称为聚合体的聚合物纳米颗粒来非侵入性诊断一种罕见而致命的脑部疾病--GM1神经节苷脂增多症的方法。这种聚合体工具的开发将提供关于患者疾病进展的实时信息，从而允许更好的临床干预。这项工作将确定酶活性作为GM1疾病进展的生物标记物在细胞和动物模型中的潜力。聚合体将在小鼠的大脑中提供实时荧光读数，与这些酶的活性水平相关，并确认疾病的进展。职业项目的研究目标与教育目标相结合，使高中教师参与研究并增加他们对科学过程的知识。我们的Come and See SC计划将把这一研究经验与教师带回学生的课堂模块的指导开发相结合，以提高南卡罗来纳州的公民科学素养。研究人员的首要职业目标是了解聚合物与中枢神经系统的相互作用。为了实现这一目标，这个职业项目旨在创建一个刺激反应聚合物(聚合体)的纳米颗粒系统，该系统可以根据与脑部疾病相关的病理变化改变其结构，以提高诊断水平。具体地说，这项建议侧重于阐明与GM1神经节苷脂沉积症相关的动态平衡变化，GM1神经节苷脂沉积症是一种溶酶体储存障碍，迫切需要诊断和监测工具。通过了解整个疾病进展过程中细胞变化和酶活性之间的关系，确认酶活性是疾病的生物标志物，可以改进诊断和监测。同时，我们开发了一种生物杂化聚合体系统，在酶的存在下响应和降解，以提供一种诊断手段。与目前仅在单个时间点执行的技术不同，这种新的生物混合系统将使在大脑中原位获取时空信息成为可能。最后，这种工具的模块化性质将允许微小的变化在整个大脑中创造诊断机会，为原位测量患者大脑中许多大分子的水平奠定基础。这项研究的目的是与提高南卡罗来纳州公民的科学素养和对科学性质的态度的教育目标相结合。项目活动的目的是培养科学公民，使他们能够舒适地做出与科学有关的决策(公民科学素养)。拟议的项目，来看看SC，为高中教师提供专业发展和研究，以提高他们的公民科学素养，这将转化为学生。该项目由生物医学系统工程(EBMS)和既定的刺激竞争研究计划(EPSCoR)共同资助。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。

The objective of this project is to develop a method to non-invasively diagnose a rare and fatal brain disease, GM1 gangliosidosis, using polymeric nanoparticles called polymersomes. The development of this polymersome tool will provide real-time information on the disease progression of the patient, allowing for better clinical interventions. The work will identify the potential of enzyme activities as biomarkers of GM1 disease progression in cellular and animal models. The polymersomes will provide real-time fluorescent read outs in the brains of mice, which correlate with these enzyme activity levels and confirm disease progression. The research objectives of the CAREER project are integrated with educational objectives to engage high school teachers in research and increase their knowledge of the scientific process. Our CoME and SEE SC program will integrate this research experience with guided development of in-class modules that teachers will bring back to their students to increase civic scientific literacy in South Carolina.The overarching career goal of the investigator is to understand the interactions of polymers with the central nervous system. Towards this goal, this CAREER project aims to create a nanoparticle system of stimuli-responsive polymers (polymersomes) that alter their structure in response to pathological changes associated with brain disease to improve diagnosis. Specifically, this proposal focuses on elucidating homeostatic changes related to GM1 gangliosidosis, a lysosomal storage disorder in drastic need of a diagnostic and monitoring tool. Diagnosis and monitoring can be improved by understanding the relationship between cellular changes and enzyme activity throughout disease progression, validating enzyme activity as a biomarker of disease. Simultaneously, we develop a biohybrid polymersome system, responding and degrading in the presence of enzymes, to provide a diagnostic measure. Unlike current techniques, executed at single time points only, this novel biohybrid system will enable the acquisition of temporospatial information in situ in the brain. Finally, the modular nature of this tool will permit small changes to create diagnostic opportunities throughout the brain, laying a foundation for measuring in situ levels of many macromolecules in patient brains. The research aims integrate with the educational goal of increasing the scientific literacy and attitudes towards the nature of science of citizens in the state of South Carolina. The project activities aim to create scientific citizens that feel comfortable making science-related policy decisions (civic scientific literacy). The proposed program, CoME and SEE SC, provides high school teachers with professional development, coupled with research, to increase their civic scientific literacy, which will translate to students.This project is jointly funded by Engineering of Biomedical Systems (EBMS) and the Established Program to Stimulate Competitive Research (EPSCoR).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.