Effect of diabetes on myelopoiesis and atherosclerosis

糖尿病对骨髓细胞生成和动脉粥样硬化的影响

• 批准号: 8617386
• 负责人: Partha Dutta
• 金额: $ 13.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-12 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617386
• 关键词: Aorta; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Biological Assay; Bone Marrow; Bromodeoxyuridine; C57BL/6 Mouse; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Characteristics; Collaborations; Complication; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Data; Dendritic Cells; Development; Diabetes Mellitus; Diabetic mouse; Enzyme-Linked Immunosorbent Assay; Fellowship; Flow Cytometry; Goals; Grant; Hematopoietic; Hematopoietic stem cells; Human; Hybrids; Immunohistochemistry; Inbred NOD Mice; Incidence; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interleukin-3; Interleukin-3 Receptor; Knowledge; Leptin; Location; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Maintenance; Marrow; Measures; Mentors; Modeling; Molecular; Monitor; Mus; Mutation; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Myelopoiesis; Myocardial Infarction; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Patients; Peptide Hydrolases; Phase; Phenotype; Play; Positioning Attribute; Production; RNA Interference; Research; Research Activity; Role; Signal Transduction; Spleen; Stem cells; Streptozocin; Stroke; Supporting Cell; Testing; Therapeutic; Therapeutic Intervention; Writing; X-Ray Computed Tomography; base; bone; cardiovascular risk factor; career development; chemokine; cranium; cytokine; diabetic patient; drug development; improved; in vivo; intravital microscopy; knock-down; monocyte; mouse model; non-diabetic; prevent; progenitor; receptor; reconstitution; research and development; stem; stem cell differentiation; stem cell niche; tomography; transcription factor

Patients with diabetes mellitus have a higher incidence of cardiovascular complications, such as myocardial infarction and stroke. Diabetic patient's most common cause of death is coronary artery disease, which is a complication of atherosclerosis. However, it is not well understood why atherosclerosis is highly prevalent in diabetic patients. In diabetic mice, we found significantly higher levels of myeloid cells and myeloid cell progenitors in the bone marrow. In a recent study, we described that hematopoietic stem and progenitor cell activation after myocardial infarction increases production of myeloid cells, leading to accelerated atherosclerosis. Based on these observations, we hypothesize that diabetes induces myeloid-biased hematopoietic stem cells (HSCs), increases myelopoiesis, and finally results in exacerbated atherosclerosis due to higher supply of monocytes to plaque. We will test this hypothesis in 3 specific aims: 1.We will investigate if diabetes induces myelopoiesis, particularly monocytopoiesis in hematopoietic organs like the spleen and bone marrow. We will also investigate if diabetes makes monocytes more aggressive. We will use streptozotocin to induce diabetes in C57BL/6 mice (model for type 1 diabetes). Mice homozygous for the obese spontaneous leptin mutation (Lepob/ob; commonly referred to as ob/ob mice) will be used as a model for type 2 diabetes. 2.We will investigate if diabetes biases differentiation of HSCs towards myeloid lineages. We will enumerate HSCs in the bone marrow and spleen, and investigate if HSCs isolated from diabetic mice have a propensity to readily differentiate into myeloid progenitors. To test the mechanism of preferential HSC differentiation towards myeloid lineages, we will investigate the role of interleukin-3 receptor (IL-3R) signaling. 3. We will knock down the receptor for macrophage colony stimulating factor (MCSF-R), responsible for maintenance and differentiation of monocyte progenitors, with an siRNA. We will investigate if MCSF-R knockdown reduces diabetes-induced myelopoiesis, resulting in amelioration of atherosclerosis. The long-term goal of the study is to identify changes at stem and progenitor cell levels in diabetes and develop therapeutic approaches to reduce cardiovascular complications in diabetic patients. To facilitate my transition from a mentored postdoctoral fellowship to a stable independent research position, the K99 phase will be conducted as integrated mentored career development and research activities, and the R00 phase will be devoted to execution of the proposed research, establishing collaborations, and writing an R01 grant.

糖尿病患者的心血管并发症发生率更高，例如心肌。 梗塞和中风。糖尿病患者最常见的死亡原因是冠状动脉疾病，这是 动脉粥样硬化的并发症。但是，尚不清楚为什么动脉粥样硬化在 糖尿病患者。在糖尿病小鼠中，我们发现髓样细胞和髓样细胞水平明显更高 骨髓中的祖细胞。在最近的一项研究中，我们描述了造血茎和祖细胞 心肌梗塞后的激活增加了髓样细胞的产生，导致加速 动脉粥样硬化。基于这些观察，我们假设糖尿病会诱导髓样偏置 造血干细胞（HSC），增加骨髓病，最终导致动脉粥样硬化恶化 由于单核细胞供应较高。我们将以3个特定目的测试这一假设：1。我们将 研究糖尿病是否诱导骨髓骨气，尤其是造血器官中的单核细胞增多症 脾脏和骨髓。我们还将研究糖尿病是否会使单核细胞更具侵略性。我们将使用 链蛋白酶诱导C57BL/6小鼠（1型糖尿病的型号）诱导糖尿病。纯合的小鼠 肥胖的自发瘦素突变（LEPOB/OB；通常称为OB/OB小鼠）将被用作模型 2型糖尿病。 2.我们将研究糖尿病是否偏向HSC偏向髓样谱系。我们 将在骨髓和脾脏中列举HSC，并研究是否从糖尿病小鼠中分离出HSC 容易区分髓样祖细胞的倾向。测试优先HSC的机制 分化向髓样谱系，我们将研究白介素-3受体（IL-3R）信号的作用。 3。我们将击倒巨噬细胞刺激因子（MCSF-R）的受体，负责 单核细胞祖细胞的维持和分化，带有siRNA。我们将调查MCSF-R是否 敲低可减少糖尿病诱导的骨髓病，从而改善动脉粥样硬化。长期 该研究的目标是鉴定糖尿病的茎和祖细胞水平的变化并发展治疗 减少糖尿病患者心血管并发症的方法。促进我从一个 指导的博士后奖学金至稳定的独立研究职位，K99阶段将进行 作为综合的指导职业发展和研究活动，R00阶段将致力于 执行拟议的研究，建立合作和撰写R01赠款。