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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 炎症细胞因子，如白介素6(IL-6)，已被证明与1型和2型糖尿病的进展有关。糖尿病期间视网膜中的IL-6水平升高。在中枢神经系统中，包括睫状神经营养因子(CNTF)和白血病抑制因子(LIF)在内的其他IL-6家族成员在缺血应激和损伤时会升高。IL-6细胞因子家族的成员不具有相同的序列同源性，但基于共同的信号受体gp130的激活而被归类在一起。由于多个配体通过gp130发出信号，它们的生物学活性存在显著重叠，而且由于gp130的配体存在于疾病的多个阶段，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gp130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gp130信号。在第一个目的中，我们将使用血管内皮细胞中gp130失活的小鼠，使用Tie2-cre转基因小鼠和loxP靶向gp130小鼠。这些小鼠将在血管内皮细胞和骨髓来源细胞中没有gp130的情况下发育。在第二个目的中，我们将使用LIFRb的蛋白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gp130信号是否可以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 LIFRb 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.