Collaborative Research: Dynamic degradation of proteins by ubiquitination provides a novel therapeutic for controlling elevated protein levels

合作研究：通过泛素化动态降解蛋白质为控制蛋白质水平升高提供了一种新的治疗方法

基本信息

批准号：
1803008
负责人：
Wilfred Chen
金额：
$ 30万
依托单位：
University of Delaware
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1803008&HistoricalAwards=false
关键词：
Collaborative Research Dynamic degradation proteins

项目摘要

The ability to tightly control protein level is critical for cell health. High levels contribute to diseases that include cancer, diabetes, dementia, and heart disease. Current treatments do not attempt to degrade excess proteins. We propose to develop a technology that triggers protein degradation and that is reversible. Activities targeted to the general public and to teachers will expand the understanding of the importance of training in science, technology, engineering and mathematics (STEM). Exposing high school and undergraduate students to hands-on laboratory research experiences will help to attract and retain students in STEM fields. Ultimately, this training will result in a globally competitive workforce.This project will develop a new and potent approach that induces protein degradation by synthetically coupling and directing the native proteasomal degradation machinery towards the desired target protein(s). We will repurpose the Cas6 family proteins as a generalizable platform for site-specific RNA binding and processing, and demonstrate their utility to provide dynamic fine-tuning of protein levels based on intracellular microRNAs (miRNAs) levels. A key challenge in creating a novel technology that can adapt to the changing cellular environment and permit the targeting of essential proteins, which presently is not possible, is to enable dynamic fine-tuning of the protein levels. Towards this end, we will evaluate different strategies to turn off the protein degradation such that the target protein can be maintained at a desirable or set level. We envision that our technology is broadly applicable to any protein and thus will impact many diseases wherein elevated proteins levels contribute to or drive their pathology.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.

严格控制蛋白质水平的能力对于细胞健康至关重要。高水平有助于包括癌症，糖尿病，痴呆和心脏病。当前的治疗方法不会试图降解多余的蛋白质。我们建议开发一种触发蛋白质降解的技术，并且是可逆的。针对公众和教师的活动将扩大对科学，技术，工程和数学（STEM）培训重要性的理解。将高中和本科生的实验室研究经验曝光将有助于吸引和留住STEM领域的学生。最终，这种训练将导致全球竞争激烈的劳动力。该项目将开发一种新的和有效的方法，该方法通过合成耦合并将本地蛋白酶体降解机制引起蛋白质降解，从而引起蛋白质降解。我们将将CAS6家族蛋白作为特定位点特异性RNA结合和加工的可推广平台重新利用，并证明其实用性基于细胞内microRNA（miRNA）水平提供蛋白质水平的动态微调。创建一种可以适应不断变化的细胞环境并允许对基本蛋白质的靶向的新技术的关键挑战，目前是不可能的，是实现动态微调蛋白质水平。为此，我们将评估不同的策略以关闭蛋白质降解，以便可以将靶蛋白保持在理想的或设定的水平。我们设想我们的技术广泛适用于任何蛋白质，因此会影响许多疾病，在这些疾病中，升高的蛋白质水平有助于或推动其病理学。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的智力优点和更广泛的评估来支持的。影响审查标准。