Effect of diabetes on myelopoiesis and atherosclerosis

糖尿病患者心血管并发症的发生率较高，如心肌梗死 脑梗塞和中风。糖尿病患者最常见的死因是冠状动脉疾病，这是一种 动脉粥样硬化的并发症。然而，目前还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，我们发现髓系细胞和髓系细胞的水平显著升高 骨髓中的祖细胞。在最近的一项研究中，我们描述了造血干细胞和祖细胞 心肌梗死后的激活增加了髓系细胞的产生，导致加速 动脉硬化。基于这些观察，我们假设糖尿病导致髓系偏向。 造血干细胞(HSCs)，增加骨髓生成，最终导致动脉粥样硬化加重 这是因为斑块中单核细胞的供应量较高。我们将在三个具体目标上检验这一假设：1.我们将 研究糖尿病是否诱导骨髓生成，特别是造血器官中的单核细胞生成 脾和骨髓。我们还将调查糖尿病是否会使单核细胞更具侵袭性。我们将使用 链脲佐菌素诱导C57BL/6小鼠糖尿病(1型糖尿病模型)。纯合子的小鼠 肥胖的自发性瘦素突变(lepob/ob；通常被称为ob/ob小鼠)将被用作 2型糖尿病。2.我们将研究糖尿病是否会使HSC向髓系细胞分化。我们 将计数骨髓和脾中的HSCs，并调查从糖尿病小鼠分离的HSCs是否有 容易分化为髓系祖细胞的倾向。检验优惠HSC的作用机制 对于髓系细胞的分化，我们将研究白细胞介素3受体(IL-3R)信号的作用。 3.我们将破坏巨噬细胞集落刺激因子受体(MCSF-R)，负责 具有siRNA的单核细胞祖细胞的维持和分化。我们将调查MCSF-R是否 基因敲除可减少糖尿病引起的骨髓生成，从而改善动脉粥样硬化。长期的 这项研究的目标是确定糖尿病患者干细胞和祖细胞水平的变化，并开发治疗方法 减少糖尿病患者心血管并发症的方法。为了促进我从一个 指导博士后奖学金到一个稳定的独立研究岗位，K99阶段将进行 作为综合辅导职业发展和研究活动，R00阶段将致力于 执行拟议的研究，建立合作关系，并撰写R01拨款。

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.