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.

军事人员由于接触各种环境而面临更高的造血突变风险。 环境危害。最近有报道称，低至2%的突变血细胞就可以产生2-4 克隆性造血功能不确定的个体心血管疾病（CVD）增加倍数 潜力（CHIP），即使没有其他风险因素。获得性激酶突变 JAK2V617F 是其中之一 与 CHIP 相关的常见突变。携带 JAK2V617F 突变体 CHIP 的个体的风险是其 12 倍 与没有任何 CHIP 相关突变的个体相比，CVD 的发生率更高。 JAK2V617F也发挥着核心作用 大多数患有骨髓增生性肿瘤（MPN）的患者，其特征是克隆干细胞疾病 由造血干细胞扩增和成熟的、通常功能失调的血细胞的过度生成所致。患者 MPN 患者会遭受许多使人衰弱的并发症，包括静脉和动脉血栓形成， 心血管事件是这些患者发病和死亡的主要原因。尽管 我们对止血和血栓形成的认识取得了实质性进展，但我们对止血和血栓形成的了解却知之甚少。 导致 MPN 患者血栓形成风险增加的机制。血管内皮细胞 在许多 MPN 患者中可以检测到携带 JAK2V617F 突变的 EC（EC）。我们最近与一个 JAK2V617F 阳性 MPN 小鼠模型，其中突变在血细胞和血管中表达 ECs 显示，小鼠出现自发性心力衰竭，并伴有血栓形成和血管病变表型。 该模型与 CHIP 相关造血突变的其他小鼠模型形成对比，在这些模型中，小鼠发育 仅当面临高脂肪饮食等危险因素时才会发生心血管疾病。这种差异表明突变的 ECs 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，加速 MPN 患者和 CHIP 患者的 CVD。尤其， 我们提出以下三个具体目标： 目标 1) 检验 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的可能性，该分子 进而导致 JAK2V617F 突变白细胞的粘附增加。目标 2) 检验假设 JAK2V617F 诱导内皮细胞过早衰老，这是 CVD 和血管疾病的主要危险因素 血栓形成。目标 3) 研究 JAK2V617F 突变 ECs 如何在小鼠模型中促进 CVD 的发展 JAK2V617F-正极芯片。血小板生成素及其受体MPL在JAK2V617F诱导中的作用 将探讨心血管功能障碍。更好地了解造血突变如何发挥作用 心血管疾病的治疗将改善我们对两种最重要的人类健康威胁——癌症的治疗 和心脏病。