Wednesday, January 15, 2025
1/15/2025
ABSTRACT Stroke is a leading cause of death and disability worldwide. Over the past few decades, there have been extensive investigations and enormous research efforts to find better therapies for stroke patients. However, many strategies that are effective in animal models have proven ineffective in clinical trials. Thus, tissue plasminogen activator (tPA) is still the only FDA-approved drug for stroke. The lack of successful bench-to-clinic translation is mainly due to two reasons, with one being the complexity of the pathology of stroke, which includes a multiplex of signaling pathways, various cell types, and both local and systemic inflammatory responses. Secondly, the prevailing clinical conditions in patients, such as hyperlipidemia, are not included in animal models of stroke. We propose that a pleiotropic target which can integrate multiple critical components in various cell types will be the key to developing effective stroke therapies by using clinically relevant animal models. In this proposal, we propose that the oxidative stress activated Ca2+-permeable TRPM2 can serve as this pleiotropic target for developing effective stroke therapies. The goal of this proposal is to investigate whether (Aim 1) and how (Aim2) TRPM2 plays a vital role in ischemic injury cascade, and to determine whether TRPM2 may serve as a pleiotropic target for ischemic stroke using the classical stroke model (Aim 1) and a clinically relevant stroke model (Aim 3). We will use state-of-the-art multidisciplinary approaches to test our hypothesis. Successful completion of this proposal will not only prove the concept that a pleiotropic target represents a new strategy for developing effective therapies for ischemic stroke, but also will provide profound insights into translational implications of developing new stroke treatment by targeting TRPM2.
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