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

• 批准号: 1802992
• 负责人: Christina Chan
• 金额: $ 30万
• 依托单位: Michigan State University
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1802992&HistoricalAwards=false
• 关键词: Collaborative; Research; Dynamic; degradation; proteins

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细胞健康至关重要。高水平会导致癌症、糖尿病、痴呆和心脏病等疾病。目前的治疗方法并不试图降解过量的蛋白质。我们建议开发一种技术，触发蛋白质降解，这是可逆的。针对公众和教师的活动将扩大对科学、技术、工程和数学培训重要性的理解。让高中生和本科生亲身体验实验室研究经验将有助于吸引和留住STEM领域的学生。本项目将开发一种新的、有效的方法，通过合成偶联诱导蛋白质降解，并将天然蛋白酶体降解机制导向所需的靶蛋白。我们将重新利用Cas6家族蛋白作为位点特异性RNA结合和加工的通用平台，并证明它们在基于细胞内microRNA（miRNAs）水平提供蛋白水平动态微调方面的实用性。在创造一种新技术，可以适应不断变化的细胞环境，并允许靶向必需蛋白质，目前是不可能的，一个关键的挑战是使蛋白质水平的动态微调。为此，我们将评估不同的策略，以关闭蛋白质降解，使目标蛋白质可以保持在一个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，从而将影响许多疾病，其中升高的蛋白质水平有助于或驱动其病理学。该奖项反映了NSF的法定使命，并已被认为值得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的支持。

项目成果

Soft surfaces induce neural differentiation via the neuron restrictive silencer factor

• DOI: 10.1016/j.bej.2022.108724
• 发表时间: 2022-11-21
• 期刊: BIOCHEMICAL ENGINEERING JOURNAL
• 影响因子: 3.9
• 作者: Thompson，Ryan;Mazur，Nick;Chan，Christina
• 通讯作者: Chan，Christina

NRSF and Its Epigenetic Effectors: New Treatments for Neurological Disease

• DOI: 10.3390/brainsci8120226
• 发表时间: 2018-12
• 期刊: Brain Sciences
• 影响因子: 3.3
• 作者: Ryan Thompson;C. Chan

Forskolin and IBMX Induce Neural Transdifferentiation of MSCs Through Downregulation of the NRSF

• DOI: 10.1038/s41598-019-39544-0
• 发表时间: 2019-02
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: Ryan Thompson;C. Casali;C. Chan