Regulation of lipid metabolism by SREBPs: A RING and a SPRING control the masters in metabolic disease
Projectomschrijving
SPRING en RING in vet metabolisme
Ons lichaam heeft cholesterol en vetten nodig, maar te veel daarvan kan metabolische- en hart- en vaatziekten veroorzaken. De onderzoekers gaan de door hen ontdekte genen SPRING en RING-finger-145 bestuderen, aangezien ze de aanmaak van cholesterol en vetten reguleren. Zij willen op basis van dit onderzoek nieuwe behandelmethoden ontwikkelen.
SPRING and a RING in lipid metabolism
Our body needs cholesterol and fat, but in excess these are harmful and cause metabolic and cardiovascular disease. In this project, the scientists will study genes they found, SPRING and RING-finger-145 which regulate cholesterol and fat production. With these studies the researchers aim to develop new treatments for lipid-related diseases.
Verslagen
Samenvatting van de aanvraag
Disturbed cholesterol and fatty acid metabolism is a key contributor to development of metabolic and cardiovascular disease. Current strategies to treat lipid disorders and ensuing metabolic consequences are inadequate, leaving an unmet therapeutic need. In order to develop novel therapeutic strategies for lipid-related conditions, it is important to uncover the mechanisms underlying (dys)regulation of lipid homeostasis.
The Sterol Regulatory Element Binding Proteins (SREBP) are the master transcriptional regulators of cholesterol and fatty acid biosynthesis. Hence, better understanding the regulatory mechanisms that control SREBPs is vital. To investigate the SREBP pathway we recently developed unique genetic screens based on the use of CRISPR/Cas9-engineered mammalian haploid cells. Combining findings from independent screens allowed us to positively identify two previously unrecognized regulators of the SREBP pathway: an unknown gene we named SREBP Regulating Gene (SPRING) and RING finger 145 (RNF145), which are the focus of this application. In exciting pilot experiments, we demonstrate that both are critical determinants of the SREBP pathway. This leads me to hypothesize that these, and yet to be identified, novel SREBP regulators play a key role in lipid homeostasis and development of metabolic and cardiovascular disease. I therefore aim to specifically:
1) Elucidate the mechanisms governing regulation of SREBPs by SPRING in metabolic and cardiovascular disease.
2) Determine the mechanisms governing regulation of SREBPs by RNF145 in metabolic and cardiovascular disease.
3) Apply our innovative genetic approach to identify and characterize other novel SREBP regulators.
These studies will enhance our understanding of SREBP regulation, and may guide development of mechanism-based strategies to treat metabolic disease. Given the centrality of the SREBP pathway, I expect the outcome of this proposal to have implications for a broad range of biomedical fields.