ROLE OF THE INTERLEUKIN 6 CYTOKINE FAMILY RECEPTOR GP130 IN DIABETES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 炎症细胞因子，如白细胞介素6（IL-6）已被证明参与1型和2型糖尿病的进展。糖尿病期间视网膜中的IL-6水平升高。在中枢神经系统中，其他IL-6家族成员，包括睫状神经营养因子（CNTF）和白血病抑制因子（LIF），在缺血应激和损伤期间升高。细胞因子的IL-6家族的成员不共享序列同源性，但基于共同信号传导受体gp 130的活化而分组在一起。由于多个配体通过gp 130信号传导，因此它们的生物活性存在显著重叠，并且由于gp 130的配体在疾病的多个阶段存在，因此同一受体的多个配体可能在疾病进展中发挥多种作用。 为了证明gp 130通路在疾病进展中的完全参与，我们提出了两种互补的方法来阻断血管内皮细胞和成年动物中的gp 130信号传导。在第一个目标中，我们将使用血管内皮细胞中gp 130失活的小鼠，使用tie 2-cre转基因小鼠和loxP靶向gp 130小鼠。这些小鼠将在血管内皮细胞和骨髓衍生细胞中经历没有gp 130的发育。 在第二个目标中，我们将使用LIFR β的蛋白质拮抗剂来阻断成年动物中神经营养性IL-6家族成员（LIF和CNTF）的活性。在这两个目标中，我们将确定阻断gp 130信号传导是否能降低糖尿病眼部并发症的严重程度和进展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Inflammatory cytokines, such as Interleukin 6 (IL-6) has been shown to be involved in the progression of both type 1 and type 2 diabetes. IL-6 levels are elevated in the retina during diabetes. In the central nervous system other IL-6 family members, including ciliary neurotrophic factor (CNTF) and Leukemia Inhibitory Factor (LIF), are elevated during ischemic stress and injury. Members of the IL-6 family of cytokines do not share sequence homology, but are grouped together based on activation of a common signaling receptor, gp130. Because multiple ligands signal through gp130, there is significant overlap in their biological activity, and since ligands of gp130 are present during multiple stages of disease it is possible that multiple ligands of the same receptor may play multiple roles in disease progression. To demonstrate the complete involvement of the gp130 pathway in disease progression we are proposing to two complimentary approaches to block gp130 signaling in vascular endothelial cells and in adult animals. In the first aim we will use mice with gp130 inactivated in vascular endothelial cells using the tie2-cre transgenic mouse and the loxP targeted gp130 mouse. These mice will undergo development without gp130 in vascular endothelial cells and bone marrow derived cells. In the second aim we will use a protein antagonist of LIFRbeta to block the activity of neurotrophic IL-6 family members (LIF and CNTF) in adult animals. In both aims we will determine whether or not blocking gp130 signaling reduces the severity and progression of diabetic complications in the eye.