Project Grant R01AI187288

The National Institute of Allergy and Infectious Diseases (NIAID) awarded a $800,005 Project Grant under the Allergy and Infectious Diseases Research program (CFDA 93.855) to The General Hospital Corporation, doing business as Massachusetts General Hospital (MGH), to conduct research on the structural basis and functional impacts of genetic variants in G-protein coupled receptors (GPCRs) associated with autoimmune diseases.

The project aims to: 1) define the structural basis for impaired function of the autoimmunity-associated GPR65 variant and potential rescue by positive allosteric modulators, 2) define the structural basis for the autoimmunity-associated PTAFR variant and its gain-of-function mechanism, and 3) discover novel GPCR variants and integrate genetics with functional mutagenesis to elucidate disease mechanisms. MGH will leverage advancements in biophysics and structural biology to investigate how coding variants in prioritized GPCRs alter protein structure, function, and downstream signaling. This research is expected to provide insights to guide development of therapeutic interventions targeting genetic mechanisms of autoimmune diseases.

The project will involve a sub-award to the University of California, San Francisco (UCSF) to perform biochemical, computational, cell biology, and structural biology experiments on the GPR65, PTAFR, and other GPCR targets identified through genetic association mapping.