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: 9172344
• 负责人: Partha Dutta
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172344
• 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; Obese Mice; 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：糖尿病患者心血管并发症的发生率较高，如心肌梗死和卒中。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。然而，为什么动脉粥样硬化在糖尿病患者中高度流行还没有很好的理解。在糖尿病小鼠中，我们发现骨髓中髓样细胞和髓样祖细胞的水平显著较高。在最近的一项研究中，我们描述了心肌梗死后造血干细胞和祖细胞的激活增加了骨髓细胞的产生，导致动脉粥样硬化加速。基于这些观察结果，我们假设糖尿病诱导骨髓偏向造血干细胞（HSC），增加骨髓生成，并最终导致动脉粥样硬化恶化，由于单核细胞的供应量增加斑块。我们将从三个方面来检验这一假说：1.我们将研究糖尿病是否诱导骨髓细胞生成，特别是造血器官如脾脏和骨髓中的单核细胞生成。我们还将研究糖尿病是否使单核细胞更具攻击性。我们将使用链脲佐菌素在C57 BL/6小鼠（1型糖尿病模型）中诱导糖尿病。肥胖自发性瘦素突变的纯合小鼠（Lepob/ob;通常称为ob/ob小鼠）将用作2型糖尿病的模型。2.我们将研究糖尿病是否会使HSC向髓系分化。我们将对骨髓和脾脏中的造血干细胞进行计数，并研究从糖尿病小鼠中分离的造血干细胞是否具有容易分化为髓系祖细胞的倾向。为了检测HSC优先向髓系分化的机制，我们将研究白细胞介素-3受体（IL-3R）信号传导的作用。 3.我们将敲低巨噬细胞集落刺激因子（MCSF-R）的受体，负责单核细胞祖细胞的维持和分化。我们将研究MCSF-R敲低是否减少糖尿病诱导的骨髓生成，从而改善动脉粥样硬化。该研究的长期目标是确定糖尿病干细胞和祖细胞水平的变化，并开发治疗方法以减少糖尿病患者的心血管并发症。为了促进我从一个指导博士后奖学金过渡到一个稳定的独立研究职位，K99阶段将作为综合指导职业发展和研究活动进行，R 00阶段将致力于执行拟议的研究，建立合作，并编写R 01赠款。