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.

军事人员由于暴露在不同的环境中，发生造血突变的风险增加。 环境危害。最近，有报道称，低至2%的突变血细胞就能产生2-4 不确定克隆性造血者心血管疾病的发生率成倍增加 潜在(筹码)，即使在没有其他风险因素的情况下也是如此。获得性激酶突变JAK2V617F是 与芯片相关的常见突变。携带JAK2V617F突变芯片的个体的风险是其他人的12倍 与没有任何芯片相关突变的个体相比，心血管疾病的风险更高。JAK2V617F也发挥着核心作用 在大多数骨髓增生性肿瘤(MPN)患者中，这是一种克隆性干细胞疾病 由于造血干细胞的扩张和成熟的、通常是功能失调的血细胞的过度生产。病人 患有MPNS的患者会出现许多令人衰弱的并发症，包括静脉和动脉血栓形成， 心血管事件是这些患者发病率和死亡率的主要原因。尽管 在我们对止血和血栓形成的了解方面取得了实质性的进展，令人惊讶的是，对 MPNS患者血栓形成风险增加的机制。血管内皮细胞 携带JAK2V617F突变的ECS可在许多MPNS患者中检测到。我们最近与一个 JAK2V617F阳性的MPN小鼠模型，突变在血细胞和血管中都有表达 ECS显示，小鼠发生了自发性心力衰竭，并伴有血栓和血管病变表型。 这个模型与其他与芯片相关的造血突变的小鼠模型进行了对比，在这些模型中，小鼠发生了 只有在受到高脂饮食等危险因素的挑战时，才会患心血管疾病。这一差异表明突变的EC可以 加速心血管功能障碍。根据这些研究，我们推测JAK2V617F突变 诱导内皮功能障碍，加速MPNS患者和CHIP患者的心血管疾病。特别是， 我们提出了以下三个具体目标：目的1)检验JAK2V617F突变 通过上调主要的EC黏附分子E-选择素来增加内皮血栓形成的可能性 进而导致JAK2V617F突变白细胞的粘附性增加。目的2)检验假设 JAK2V617F诱导血管内皮细胞早衰是心血管疾病和血管病变的主要危险因素 血栓形成。目的3)研究JAK2V617F突变的内皮细胞在小鼠脑血管病模型中的作用 JAK2V617F阳性芯片。促血小板生成素及其受体MPL在JAK2V617F诱导中的作用 本课程将探讨心血管功能障碍。更好地了解造血突变是如何起作用的 心血管疾病将改善我们对癌症这两个最重要的人类健康威胁的治疗 和心脏病。