This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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