Thomas Brett, PhD

Associate Professor, WashU Medicine

Investigate the molecular mechanisms of inflammatory signaling in diseases hallmarked by chronic inflammation

My lab primarily uses structural biology, biophysics, and cellular techniques to investigate the molecular mechanisms of inflammatory signaling in diseases hallmarked by chronic inflammation. In the past five years, we have focused on investigating how Alzheimer’s Disease (AD) risk variant point mutations in TREM2 impact its structure, stability, intermolecular interactions, and function. We determined the first crystal structure of TREM2 and carried out initial comprehensive structural and biophysical analysis of TREM2 AD risk variants, showing they inhibit binding to glycosaminoglycans (GAGs). These results were recently published in Elife. We have since investigated the binding of TREM2 to other proteins linked to AD pathogenesis, Aβ and ApoE, and found that AD risk variants do not grossly impact binding to these ligands, and we mapped a unique binding site for ApoE on TREM2. We plan to extend this work to map the interactions that TREM2 has with multiple ligands that may contribute to AD pathogenesis. The work here will contribute to providing a framework for developing therapeutics that prevent AD pathogenesis by correcting or enhancing TREM2 function. In addition, in further studies we are applying our structural and biophysical approach to investigate other risk factors for the development of AD, including PLD3 and MS4A. Our long-term goal is to decipher the structural and molecular biophysical mechanisms by which these proteins contribute to neuronal health and development of AD so that disease-alleviating treatments can be designed. These goals overlap with the Hope Center mission of pursuing the elucidation of disease mechanisms that can lead to the development of new treatments.

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