Targeted PDE4 inhibition to counteract neuroinflammation: a stroke of genius. (R-12217)

Ischemic stroke, meaning brain tissue loss due to a sudden blood flow occlusion, is one of the most common causes of death and disability worldwide. Current treatments are only applicable to a small subset of patients, highlighting the urgent need for more effective stroke therapies. Neuroinflammation is a major pathological event involved in the process of ischemic injury. Therefore, I aim to target this event by using a new therapy namely selective phosphodiesterase 4B (PDE4B) inhibition. Pan-inhibition of PDE4 has therapeutic effects in mouse models of brain ischemia. However, due to severe emetic side effects, these agents are not fit for clinical use at their effective concentration. Therefore, it will be my endeavor to study whether PDE4B inhibition reduces neuroinflammation and induces functional recovery after ischemic stroke. I will also focus on solving the current knowledge gaps: 1. Which are the main cellular targets of the innate immune system of PDE4B inhibitors? 2. Which PDE4B isoforms specifically are involved in the neuroinflammatory process after stroke? I will not only study these PDE4B isoforms in ischemic mouse models but also using human brain biopts and human cell-based functional tests. This project will lead to the identification of the specific PDE4B isoforms involved in the neuroinflammatory process after stroke and will pave the way for the design of an innovative therapeutic to promote functional recovery after stroke.

Keywords:Innate immunity, Ischemic stroke, Phosphodiesterases

Disciplines:Regenerative medicine not elsewhere classified