Clonal Haematopoiesis in Ischemic Stroke

中风是世界范围内导致死亡的主要原因之一，常常导致终身残疾。在这个研究联盟中，我们想要研究所谓的克隆造血在缺血性中风（即由脑血管闭塞引起的中风，随后的脑梗死）中的作用。而克隆造血则是一种循环血细胞的失衡，随着年龄的增长而更频繁地发生，并且有肿瘤发展和血管事件（如中风）的风险。如果造血干细胞发生突变，可能会导致某些细胞过度生长，这被称为克隆扩增。我们已经能够证明，在一组首次缺血性中风的患者中，由TET2基因获得性突变引起的克隆造血患者在未来发生第二次血管事件或死亡的风险更高。然而，完全未知的是，这种克隆扩增的血细胞是否会像克隆造血一样，在中风后进入大脑并造成额外的脑损伤。我们现在想在一个具有互补研究专长的科学家联盟中研究这个实验中风模型。在这里，我们将产生具有不同水平的克隆扩增tet2突变血细胞的小鼠，并将它们暴露于实验性中风。随后，我们将研究突变细胞向大脑的迁移，以及由此导致的大脑组织损伤和动物的功能恢复。在第二步中，我们将用阻断炎症的药物对这些动物进行克隆造血治疗。我们相信，专注于克隆造血，特别是测试患者的突变克隆大小，将确定一个共同的危险因素，可以作为预防和治疗中风的治疗目标。

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.