Prerna Tiwari, MS
Development of Small Molecule TREM1 Inhibitors to Treat Global Ischemia
Abstract
Global cerebral ischemia, a severe form of stroke often caused by cardiac arrest, leads to cognitive deficits or death. To date, there is no effective treatment for neurodegeneration and cognitive impairment associated with global ischemia. TREM1, a membrane immune receptor, amplifies proinflammatory responses and contributes to neuroinflammation. Our recent studies showed that global ischemia activates TREM1 in the hippocampal CA1 in rats, and its inhibition by LR12 shows neuroprotection. However, current inhibitors have limitations including poor cell permeability and short half-life. To overcome these limitations, we propose a small molecule drug discovery approach to develop TREM1 inhibitors. We showed that GJ079 attenuates ischemia-induced glial activation and neuronal death, in vivo, demonstrating its neuroprotective potential. These findings suggest that the structural modifications of GJ079 could lead to development of non-toxic, bioavailable, and potent TREM1 inhibitors.
Receiving this fellowship is incredibly meaningful to me. It supports my commitment to drug discovery and motivates me to pursue rigorous, impactful research that can advance therapeutic innovation and ultimately improve outcomes for patients.
