image: Djamel Lebeche, PhD
Credit: UT Health Science Center
The National Institute of Neurological Disorders and Stroke has awarded $2.18 million to two researchers at the University of Tennessee Health Science Center for a project focused on a new drug treatment to protect the brain after a stroke. The principal investigators are Djamel Lebeche, PhD, professor in the Department of Physiology, and Tauheed Ishrat, PhD, associate professor in the Department of Anatomy and Neurobiology.
Type 2 diabetic patients are two to six times more likely to suffer from an acute ischemic stroke. These patients also face additional complications such as blood-brain barrier leakage, swelling, bleeding, and poor recovery after a stroke. Despite recent medical advances, finding effective ways to reduce these risks remains a top priority.
Dr. Lebeche's research focuses on a major factor in diabetes-induced brain injury: the disruption of normal calcium balance in the body. The SERCA2 pump, which regulates calcium levels inside cells, is crucial for maintaining this balance. Diabetes and stroke reduce the function and expression of SERCA2, leading to increased calcium levels in cells. This increase contributes to cell death and tissue damage through stress on the endoplasmic reticulum (ER), mitochondrial dysfunction, inflammation, and oxidative stress.
Dr. Lebeche's and Dr. Ishrat’s project will investigate the benefits and mechanisms of a new small molecule, CDN1163, which activates SERCA2, in the setting of diabetic stroke. Preliminary data show that diabetic and normal mice have lower SERCA2 levels after a stroke, but treatment with CDN1163 reduces brain damage and improves recovery.
“Our research goal is to identify suitable drug targets to aid in discovering novel therapies to mitigate neurovascular damage and improve stroke outcomes in diabetic patients,” Dr. Ishrat said.
The researchers’ hypothesis is that activating SERCA2 after a stroke will correct calcium imbalances caused by diabetes, reduce ER stress and mitochondrial dysfunction, and improve neurovascular and functional recovery. Using advanced techniques and models, including single-cell RNA sequencing, they aim to understand how CDN1163 protects the brain in diabetic stroke injury.
“Restoring calcium homeostasis through SERCA2 activation could have pleiotropic effects and thus be more effective than targeting single action for this highly debilitating disease that has limited treatment options as well as a narrow and acute window for treatment,” Dr. Lebeche said.