Signaling Status in Lupus

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Lupus is a complex autoimmune disease with substantial morbidity and mortality, where an aberrant immune system causes organ damage affecting the joints, brain, skin and kidneys. However, the molecular mechanism underlying the pathogenesis of lupus is largely unknown. Previous studies have shown immune cells, such as B cells, T cells and myeloid cells in lupus are hyper-proliferative and hyperactive during disease. Recent genetic studies have uncovered quite a few important lupus genes, including innate immune responses related genes, such as IRF5, STAT4 and IRAK1 etc; B cell signaling related genes, such as BLK, BANK1, LYN and Ly108 etc; and T cell activation related genes, such as PTPN22, HLA-DR, and PDCD1 etc. At the same time, we found several signaling axes, including PI3K/AKT/mTOR, MEK1/Erk1/2, p38, NF-:B, multiple Bcl-2 family members, and cell-cycle, to be aberrant in lymphocytes from lupus mouse models compared to normal controls. This finding is important because it has revealed some good therapeutic targets in murine lupus. In the completed work we have shown that blocking AKT/mTOR activation can be therapeutic in murine lupus. Recently, I have also shown that MAPK and NF-:B activation are also good therapeutic targets, using CDDO-me and NEMO-binding peptides as treatment agents (manuscripts in preparation). Finally, I have recently defined several T-cell signaling pathways that are also upregulated in murine lupus (manuscript in preparation). Another important reason to propose this study is based on our recent whole kinome assay results, which is exciting since it reflects the functional status of all kinases in lupus lymphocytes. Importantly, this functional screen confirmed some of our published data using western blots. Besides, this comprehensive kinome screen has also revealed some novel and important signaling molecules which might be of pathogenic importance in guiding lupus development. Collectively, these studies have shown that signaling molecules may be good treatment targets in lupus. The goal of this grant is to translate these findings to human SLE. In this study, we have 2 specific aims. Aim 1: To study the expression of Aurora A, Plk1, PKR, RSK3 and RIPK3 in murine lupus leukocytes, extrapolating from the findings of our recent comprehensive kinome screens. Aim 2: To study the expression of selected signaling axes (already established to be elevated in murine lupus) within the leukocytes of SLE patients, using "Reverse phase signaling array", a comprehensive screening platform. PUBLIC HEALTH RELEVANCE: Narrative: Lupus is a highly complex autoimmune disease and the mechanism of the disease is unknown. We and other laboratories have shown some signaling molecules, particularly kinases are upregulated in lupus mice. In this study, we will validate these potentially interesting molecules by using novel biochemical and proteomic approaches, in order to draw a signaling network that might contribute to the development of lupus. .