Endothelial dysfunction in clonal hematopoiesis and its contribution to cardiovascular complications

克隆造血中的内皮功能障碍及其对心血管并发症的影响

• 批准号: 10481299
• 负责人: Huichun Zhan
• 金额: --
• 依托单位: NORTHPORT VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481299
• 关键词: Acceleration; Adhesions; Adult; Affect; Age; Aorta; Binding; Blood Cells; Blood Vessels; CDKN2A gene; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Adhesion Molecules; Cell Aging; Cell Cycle; Cell Line; Cell physiology; Coronary artery; Development; Diet; Disease; E-Selectin; Echocardiography; Elderly; Endothelial Cells; Endothelium; Environmental Hazards; Event; Exposure to; Functional disorder; Genes; Genetic; Goals; Harvest; Health; Heart; Heart Diseases; Heart failure; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemostatic function; High Fat Diet; Hospitalization; Human; In Vitro; Incidence; Individual; Induced Mutation; JAK2 gene; Knock-out; Leukocytes; Lung; MPL gene; Malignant Neoplasms; Measures; Mediating; Methods; Military Personnel; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Myeloproliferative disease; Pathology; Patients; Persons; Phenotype; Phosphotransferases; Play; Production; Proteins; Reporting; Risk; Risk Factors; Role; Signal Transduction; Site; Small Interfering RNA; Testing; Thrombopoietin; Thrombosis; Time; Toxic Environmental Substances; Transgenic Organisms; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Venous; Veterans; Work; beta-Galactosidase; cardiovascular disorder risk; cardiovascular risk factor; cell type; endothelial dysfunction; experimental study; hematopoietic stem cell expansion; human disease; human model; improved; in vivo; induced pluripotent stem cell; inhibitor; insight; knock-down; mortality; mouse model; mutant; premature; receptor; senescence; stem; stem cells; thrombogenesis

Military personnel are at an increased risk of developing hematopoietic mutations due to their exposure to various environmental hazards. Recently, it has been reported that as low as 2% mutant blood cells can produce a 2-4 fold increase in cardiovascular diseases (CVDs) in individuals with clonal hematopoiesis of indeterminate potential (CHIP), even in the absence of other risk factors. The acquired kinase mutation JAK2V617F is one of the common mutations associated with CHIP. Individuals with JAK2V617F mutant CHIP have 12 times the risk of CVDs compared to individuals without any CHIP-associated mutation. JAK2V617F also plays a central role in most patients with myeloproliferative neoplasms (MPNs), which are clonal stem cell disorders characterized by hematopoietic stem cell expansion and overproduction of mature, often dysfunctional blood cells. Patients with MPNs suffer from many debilitating complications including both venous and arterial thrombosis, with cardiovascular events being the leading cause of morbidity and mortality in these patients. Despite the substantial progress in our understanding of hemostasis and thrombosis, remarkably little is known about the mechanisms that contribute to the increased thrombosis risk in patients with MPNs. Vascular endothelial cells (ECs) carrying the JAK2V617F mutation can be detected in many patients with MPNs. Our recent work with a JAK2V617F-positive murine model of MPN, in which the mutation is expressed in both blood cells and vascular ECs, showed that the mice developed spontaneous heart failure with a thrombosis and vasculopathy phenotype. This model contrasts other murine models of CHIP-associated hematopoietic mutations, in which mice develop CVDs only when challenged with risk factors such as high-fat diet. This difference suggests that mutant ECs can accelerate cardiovascular dysfunction. Based on these studies, we hypothesize that the JAK2V617F mutation induces endothelial dysfunction to accelerate CVDs in patients with MPNs and in people with CHIP. In particular, we propose the following three specific aims: Aim 1) To test the hypothesis that the JAK2V617F mutation increases endothelial thrombogenic potential by upregulating a major EC adhesion molecule E-selectin, which in turn leads to increased adhesion of JAK2V617F mutant leukocytes. Aim 2) To test the hypothesis that JAK2V617F induces premature endothelial senescence, which is a major risk factor for CVDs and vascular thrombosis. Aim 3) To study how JAK2V617F mutant ECs promote the development of CVD in a murine model of JAK2V617F-positive CHIP. The roles of thrombopoietin and its receptor MPL in JAK2V617F-induced cardiovascular dysfunction will be explored. A better understanding of how hematopoietic mutations contribute to cardiovascular diseases will improve our treatment of two of the most important human health threats, cancer and heart disease.

军事人员由于暴露于各种而出现造血突变的风险增加 环境危害。最近，据报道，低至2％的突变血细胞可以产生2-4 不确定的克隆造血症患者的心血管疾病（CVD）的倍数增加 潜力（芯片），即使没有其他风险因素。获得的激酶突变JAK2V617F是 与芯片相关的常见突变。具有JAK2V617F突变芯片的人的风险是12倍 与没有任何芯片相关突变的个体相比，CVD的CVD。 JAK2V617F也起着核心作用 在大多数患有骨髓增生性肿瘤（MPN）的患者中，是克隆干细胞疾病的特征 通过造血干细胞的膨胀和成熟的，通常功能失调的血细胞生产。患者 MPN遭受许多令人衰弱的并发症，包括静脉和动脉血栓形成，都有 心血管事件是这些患者发病率和死亡率的主要原因。尽管有 在我们对止血和血栓形成的理解方面的实质性进展，关于 导致MPN患者血栓形成风险增加的机制。血管内皮细胞 （EC）在许多MPN患者中可以检测到携带JAK2V617F突变。我们最近与 MPN的JAK2V617F阳性鼠模型，其中突变在血细胞和血管中均表达 ECS表明，小鼠患有血栓形成和血管病表型出现自发心力衰竭。 该模型与芯片相关造血突变的其他鼠模型进行了对比，其中小鼠发展 仅在面对诸如高脂饮食之类的危险因素挑战时，CVD。这种差异表明突变EC可以 加速心血管功能障碍。基于这些研究，我们假设JAK2V617F突变 诱导内皮功能障碍在MPN和芯片患者中加速CVD。尤其， 我们提出以下三个特定目的：目标1）测试JAK2V617F突变的假设 通过上调主要的EC粘附分子E-选择素来增加内皮血栓形成潜力，该分子E-选择素 进而导致JAK2V617F突变白细胞的粘附增加。目标2）检验以下假设 JAK2V617F诱导过早的内皮衰老，这是CVD和血管的主要危险因素 血栓形成。目标3）研究JAK2V617F突变体如何促进鼠模型中CVD的发展 JAK2V617F阳性芯片的血小板生物素及其受体MPL在JAK2V617F诱导的作用 将探索心血管功能障碍。更好地了解造血突变如何贡献 到心血管疾病将改善我们对两个最重要的人类健康威胁的治疗 和心脏病。