Clonal Haematopoiesis in Ischemic Stroke

• Applicants: Professor Dr. Matthias Endres; Professor Dr. Christoph Harms
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 522473931

Stroke is one of the leading causes of death worldwide and often leads to lifelong disability. In this research consortium, we would like to investigate the role of so-called clonal hematopoiesis in ischemic stroke (i.e. stroke caused by occlusion of a cerebral vessel with subsequent infarction of the brain). Clonal hematopoiesis, in turn, is an imbalance of circulating blood cells that occurs more frequently with age and is a risk for both tumor development and vascular events such as stroke. If hematopoietic stem cells mutate, this might lead to overgrowth of certain cells that is called clonal expansion. We have been able to show, in a cohort of patients who have suffered a first ischemic stroke that patients who have clonal hematopoiesis caused by acquired mutations in the gene TET2 are at higher risk for a second vascular event or death in the future. What is completely unknown, however, is whether such clonally expanded blood cells, as they occur in clonal hematopoiesis, can enter the brain after a stroke and cause additional brain damage. We now want to investigate this in a consortium of scientists with complementary research expertise in an experimental stroke model. Here, we will generate mice with different levels of clonally expanded Tet2-mutated blood cells and expose them to an experimental stroke. Subsequently, we will investigate the migration of the mutant cells into the brain, furthermore the resulting tissue damage in the brain as well as the functional recovery of the animals. In a second step, we will then specifically treat these animals with clonal hematopoiesis with drugs that block inflammation. We are confident that focusing on clonal hematopoiesis and, in particular, testing patients for their mutant clone size, will identify a common risk factor that can be therapeutically targeted for both prevention and treatment of stroke.

• DFG Programme: Research Grants
• International Connection: France, Israel, Poland
• Cooperation Partners: Professor Steffen Jung, Ph.D.; Daniel Lewandowski, Ph.D.; Anna Malik, Ph.D.