The research project focuses on uncovering the mysteries surrounding orphan G protein-coupled receptors (GPCRs), which are essential membrane proteins that play a crucial role in various bodily functions. GPCRs make up about 30% of all drug targets, yet there are over 200 of them, including 120 orphan receptors, whose functions remain unknown.
The primary goal of the study is to advance our understanding of these orphan GPCRs and their implications for health and disease. The research plan involves three main objectives:
Developing Biophysical Readouts: Creating methods to examine how these receptors bind to ligands, change their shapes, and activate, which are crucial aspects of their functioning.
Discovering New Ligands: Using computational methods to screen large compound libraries in silico, aiming to find new selective ligands for orphan GPCRs. This step is vital for potential drug development.
Investigating Mutant Effects: Studying how normal and disease-associated mutations of GPCRs affect cells both in laboratory settings (in vitro) and within living organisms (in vivo).
The choice to study orphan GPCRs is significant because despite their prevalence, they haven’t been linked to any specific drugs or diseases. This suggests a potential untapped therapeutic resource among these receptors. The project builds on the researcher’s past contributions, including the characterization of GPR61 and preliminary work on GPR183. The methodology involves a multidisciplinary approach, combining cell biology, computational biology, genome editing (CRISPR-Cas9), and chemical biology. Experimental models include cell cultures, mouse models, and advanced screening techniques.
The ultimate goal is to not only advance scientific knowledge about these receptors but also to identify potential targets for therapy in blood cancer and obesity. The research’s significance lies in its potential to contribute both to fundamental science and practical applications, with the long-term aim of developing new therapies based on a deeper understanding of orphan GPCRs.