CRISPR-mediated Simultaneous Activation of Endeogenous GDF15 and UCP1 in Skeletal Muscle to Treat Isulin Resistance and Obesity

Contact: Dr. Kornelia Johann

Funding: German Center for Diabetes Research (DZD)

CRISPR/Cas9-associated technologies have revolutionized genome editing (Doudna & Charpentier, 2014). Beyond gene editing, the CRISPR/Cas9 technology offers a versatile sequence-specific gene regulation toolset, by using a nuclease-deficient Cas9 (dCas9), which was designed not to cleave DNA while still maintaining DNA-binding proficiency when directed by a guide RNA (gRNA). Transcription activators can be tethered to dCas9/gRNA creating a powerful tool - called CRISPR-mediated activation (CRISPRa) - to increase expression of endogenous genes (Dominguez et al., 2016). CRISPRa can upregulate multiple genes at once through the co-delivery of multiple gRNAs

This DZD-funded project uses novel, specific and reversible genetic tools to mobilize endogenous defenses against diabetes and obesity. We will apply a new CRISPR gene activation technology to upregulate Ucp1 and Gdf15 gene expression in skeletal muscle of insulin-resistant, obese mice. We will test the hypothesis that this simultaneous induction of Ucp1 and Gdf15 will correct insulin resistance and obesity by decreasing appetite and increasing energy expenditure and glucose utilization. Developing a mutation-independent epigenetic strategy lowers the barrier for potential future clinical applications.