Julia Bleier, PhD
Mechanism and Manipulation of Metabotropic Glutamate Receptor 5 Allostery
Abstract
Metabotropic glutamate receptor 5 (mGluR5) is a key regulator of brain function and mGluR5 inhibition is a promising therapeutic strategy for several neuropsychiatric disorders. However, clinical development of mGluR5 inhibitors has been limited by poor selectivity, efficacy, and adverse effects. The proposed project aims to overcome these challenges by characterizing a newly developed negative allosteric nanobody, Nb40. Using an integrative approach combining pharmacology, biochemistry, and structural biology I will define the functional and structural mechanism of Nb40-mediated inhibition. I will leverage Nb40 as a tool to identify novel small molecule inhibitors of mGluR5 and mGluR1/5 through DNA-encoded library screening. This interdisciplinary approach aims to reveal new modes of allosteric regulation and candidate modulators, paving the way for safer, more effective, and selective therapies for disorders such as anxiety, autism spectrum disorders, and Parkinson’s disease.
This award will support my mechanistic studies of metabotropic glutamate receptors and allow me to expand the scope of my work towards the development of novel modulators.
