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

Michigan State University, East Lansing MI

Investigators

Abstract

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.