Clonal Haematopoiesis in Ischemic Stroke

中风是世界范围内主要的死亡原因之一，经常导致终生残疾。在这个研究联盟中，我们想要研究所谓的克隆性造血在缺血性中风(即由脑血管闭塞并随后的脑梗塞引起的中风)中的作用。反过来，克隆性造血是一种循环血细胞的失衡，随着年龄的增长发生的频率更高，是肿瘤发展和中风等血管事件的风险。如果造血干细胞发生突变，可能会导致某些细胞过度生长，这被称为克隆性扩增。我们已经能够在一组遭受第一次缺血性中风的患者中表明，由于基因TET2的获得性突变而导致克隆性造血的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，这种克隆性扩增的血细胞是否会在中风后进入大脑，造成额外的脑损伤。我们现在想要在一个科学家联盟中对此进行研究，这些科学家在实验性中风模型中具有互补的研究专长。在这里，我们将用不同水平的克隆性扩增的TET2突变血细胞培养小鼠，并将它们暴露在实验性中风中。随后，我们将研究突变细胞向脑内的迁移，进而对脑组织造成的损伤以及动物的功能恢复。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靶点。

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.