Bone Marrow Neuropathy Drives Diabetic Retinopathy

骨髓神经病变导致糖尿病视网膜病变

• 批准号: 8735950
• 负责人: Steven F Abcouwer
• 金额: $ 45.24万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-07 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735950
• 关键词: Address; Adhesions; Adoptive Transfer; Adult; Age; Behavior; Biological Models; Blindness; Blood Circulation; Blood Vessels; Blood capillaries; Bone Marrow; Bone Marrow Cells; CCL2 gene; CX3CL1 gene; Calcitonin Gene-Related Peptide; Capillary Permeability; Cell Count; Cell Culture Techniques; Cells; Chemicals; Chemotactic Factors; Chimera organism; Circadian Rhythms; Coupled; Denervation; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Dropout; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Equilibrium; Erythrocytes; Exhibits; FCGR3B gene; Flow Cytometry; Fractalkine; Functional disorder; Funding; Generations; Glucose; Hematopoiesis; Hematopoietic stem cells; Human; Immunohistochemistry; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Lead; Leukostasis; Ligands; Link; Location; Macrophage Colony-Stimulating Factor; Microglia; Microvascular Dysfunction; Modeling; Mus; Neuroglia; Neurons; Neuropathy; Neuropeptides; Neurotransmitters; Norepinephrine; Operative Surgical Procedures; Outcome; Pathogenesis; Pathology; Permeability; Phase; Physiology; Population; Prevention; Production; Property; Proteins; Recruitment Activity; Regulation; Retina; Retinal; Role; Signal Transduction; Simulate; Source; Stem cells; Stromal Cells; Substance P; Surface Antigens; Testing; Therapeutic; Time; Wild Type Mouse; Work; base; bone; capillary; chemokine; cytokine; diabetic; immunoreactivity; in vivo; macroglia; monocyte; nerve supply; noradrenergic; novel; prevent; progenitor; receptor; relating to nervous system; repaired; restoration; retina circulation; type I diabetic

DESCRIPTION (provided by applicant): In the previous funding period, we demonstrated that diabetic individuals and mice demonstrate dysfunctional endothelial progenitor cells. These bone marrow (BM) derived cells are released into the circulation in an abnormal manner due to diabetes-induced BM neuropathy. This BM neuropathy leads to dysregulation in the circadian release of these cells into the circulation. These BM changes precede development of diabetic retinopathy (DR) linking BM neuropathy for the first time to DR. Diabetic BM supernatants, but not control, contain high levels of monocyte/macrophage-colony stimulating factor (M-CSF) and diabetic mice exhibit an increase number of monocytes in the retina and circulation. Based on these findings, we hypothesize that: Diabetic BM denervation initiates HSC/progenitor dysfunction that leads to an increase in total monocytes generated, this, coupled with increased expression of CCL2 (monocyte chemoattractent protein-1) by retinal glia results in excessive levels of the pro-inflammatory (M1) monocytes in the diabetic retina. In addition, diminished levels of CX3CL1 (fractalkine) expression by dysfunctional neurons heightens the inflammatory response of resident microglia. This imbalance leads to a neural inflammation that accelerates DR pathogenesis. We will test this hypothesis both in vitro and in vivo through the simultaneous exploration of the following aims: Aim 1: To determine whether diabetes induced BM neuropathy is responsible for increased M-CSF production by BM stromal cells which shifts hematopoiesis towards generation of excessive numbers of monocytes, in particular pro-inflammatory Gr1+/CCR2+/CX3CR1lo monocytes, rather than the protective Gr1-/CCR2-/CX3CR1hi monocytes. Aim 2: To determine the roles of CCL2 and CX3CL1 in DR inflammation and to test whether restoration of the balance of CCR2+CX3CR1lo and CCR2-/CX3CR1hi monocytes and simultaneous restoration of levels of endothelial progenitors to retinal vasculature will prevent o reverse DR in T1D mice. Aim 3: Our hypothesis predicts that circulating pro- inflammatory Gr1+/CCR2+i/CX3CR1lo cells will cause endothelial cell activation, promote leukostasis and result in enhanced retinal permeability whereas Gr1-/CCR2-/CX3CR1hi cells will protect the BRB in diabetes. We will examine the effects of manipulating these subsets on the progression of DR. Targeting monocyte subtypes may represent an ideal strategy for DR prevention and treatment. CellMax?

描述（由申请人提供）：在之前的资助期间，我们证明糖尿病个体和小鼠表现出功能失调的内皮祖细胞。由于糖尿病引起的 BM 神经病变，这些骨髓 (BM) 来源的细胞以异常方式释放到循环中。这种骨髓神经病变导致这些细胞进入循环的昼夜节律释放失调。这些 BM 变化先于糖尿病视网膜病变 (DR) 的发展，首次将 BM 神经病变与 DR 联系起来。糖尿病骨髓上清液（但对照组除外）含有高水平的单核细胞/巨噬细胞集落刺激因子（M-CSF），并且糖尿病小鼠在视网膜和循环中表现出单核细胞数量增加。基于这些发现，我们假设：糖尿病BM去神经启动HSC/祖细胞功能障碍，导致单核细胞总数增加，再加上视网膜神经胶质细胞CCL2（单核细胞趋化蛋白-1）表达增加，导致糖尿病视网膜中促炎（M1）单核细胞水平过高。此外，功能失调的神经元的 CX3CL1 (fractalkine) 表达水平降低会加剧驻留小胶质细胞的炎症反应。这种不平衡会导致神经炎症，从而加速 DR 的发病机制。我们将通过同时探索以下目标，在体外和体内检验这一假设： 目标 1：确定糖尿病引起的 BM 神经病变是否与 BM 基质细胞产生的 M-CSF 增加有关，从而使造血作用转向生成过量单核细胞，特别是促炎性 Gr1+/CCR2+/CX3CR1lo 单核细胞，而不是单核细胞。 保护性 Gr1-/CCR2-/CX3CR1hi 单核细胞。目标 2：确定 CCL2 和 CX3CL1 在 DR 炎症中的作用，并测试 CCR2+CX3CR1lo 和 CCR2-/CX3CR1hi 单核细胞平衡的恢复以及视网膜血管系统内皮祖细胞水平的同时恢复是否会阻止 T1D 小鼠逆转 DR。目标 3：我们的假设预测，循环促炎性 Gr1+/CCR2+i/CX3CR1lo 细胞将引起内皮细胞活化，促进白细胞停滞并导致视网膜通透性增强，而 Gr1-/CCR2-/CX3CR1hi 细胞将保护糖尿病中的 BRB。我们将研究操纵这些子集对 DR 进展的影响。针对单核细胞亚型可能是 DR 预防和治疗的理想策略。细胞最大？