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

职业：诊断无法诊断的疾病：利用酶上调来探测神经性溶酶体贮积病的细胞行为

• 批准号: 2047697
• 负责人: Jessica Larsen
• 金额: $ 51.6万
• 依托单位: Clemson University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2047697&HistoricalAwards=false
• 关键词: CAREER; Diagnosing; Undiagnosable; Using; Enzyme

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.

该项目的目的是开发一种方法，使用称为聚合物纳米颗粒的聚合物纳米颗粒非侵入性诊断一种罕见的致命性脑部疾病，GM1神经节苷脂沉积症。这种聚合物体工具的开发将提供有关患者疾病进展的实时信息，从而可以更好地进行临床干预。这项工作将确定酶活性作为细胞和动物模型中GM1疾病进展生物标志物的潜力。聚合物囊泡将在小鼠大脑中提供实时荧光读数，这与这些酶活性水平相关，并确认疾病进展。CAREER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了解。我们的COME和SEE SC计划将整合这种研究经验与课堂模块的指导开发，教师将带回给学生，以提高南卡罗来纳州的公民科学素养。调查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，该CAREER项目旨在创建一种刺激响应聚合物（聚合物囊泡）的纳米颗粒系统，该系统可以改变其结构以响应与脑部疾病相关的病理变化，以改善诊断。具体而言，该提案的重点是阐明与GM1神经节苷脂沉积症相关的稳态变化，这是一种迫切需要诊断和监测工具的溶酶体贮积症。通过了解疾病进展过程中细胞变化与酶活性之间的关系，可以改善诊断和监测，验证酶活性作为疾病的生物标志物。同时，我们开发了一种生物杂交聚合物系统，在酶的存在下响应和降解，以提供诊断措施。与目前仅在单个时间点执行的技术不同，这种新型生物混合系统将能够在大脑中原位获取时空信息。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，为测量患者大脑中许多大分子的原位水平奠定基础。该研究旨在与提高南卡罗来纳州公民的科学素养和对科学本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，使他们能够放心地作出与科学有关的政策决定（公民科学素养）。拟议的计划，COME和SEE SC，提供高中教师的专业发展，加上研究，以提高他们的公民科学素养，该项目由生物医学系统工程（EBMS）和刺激竞争性研究的既定计划（EPSCoR）联合资助。该奖项反映了NSF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。