Using SigPathway, additional members of the complement pathway

Using SigPathway, additional members of the complement pathway C8, CFH and CFD were identified. Treatment with sirolimus returned the expression of the C3 and C1q to asymptomatic levels, while C4 in the classical pathway remained elevated. A critical signalling pathway involved in mediating an inflamma tory response is the JAK STAT and MAP kinase pathway. Increased levels of transcripts for pathway members including JAK3, STAT3, SOCS3, PTPN1, CDKN1A, RRAS and MAPK1 were observed in nephritis. After treatment with sirolimus these pathways exhibit transcriptional expression levels similar to asymptomatic levels. Rapalog mTOR canonical pathway and links to mouse lupus nephritis genes Networks were built in an effort to understand the broad rang ing beneficial effects of the mTOR pathway inhibitor, sirolimus, in NZBW lupus nephritis.
The first step in this process was to build a rapalog mTOR pathway. This pathway consisted selleck chemical STA-9090 of the mTORC1 complex, the mTORC2 com plex, the immediate downstream targets of mTORRPS6KB1 and RPS6KB2, and the upstream effec tors of mTORAKT1, AKT2, TSC1, TSC2. In addition, rapal ogs, such as sirolimus, temsirolimus and everolimus as well as all members of the immunophilin protein family that bind to the immunosuppressants FK506 and rapamycin, were included in the rapalog mTOR pathway. Downstream connectivity of the rapalog mTOR pathway to the 387 lupus nephritis genes was explored using the IPA. Of the 387 genes, 32 can be placed immediately downstream of the rapalog mTOR pathway. An additional 25 of these are connected to the pathway through various types of functional protein interactions.
Therefore, selleck chemicals based on curated protein abt-263 chemical structure protein and drug protein interactions in the literature we determined that about 15% of the identified 387 nephritis genes interact with components of the rapalog mTOR pathway. We therefore posed the ques tion Of the genes linked to lupus in the published literature, how many can be placed in the rapalog mTOR pathwayUsing curated findings in IPA, at least 50% of the known lupus associated genes in IPA and Metacore interact with components of the rapalog mTOR pathway. The large num bers of connections between the lupus nephritis genes we identified, the rapalog mTOR pathway, and previously identi fied genes associated with lupus are shown schematically in Figure 11. The individual genes in each of these categories are listed in Additional file 4. Building the mTOR pathway interactome All proteins known to interact with members of the rapalog mTOR pathway, upstream and downstream were used to cre ate the mTOR pathway interactome, consisting of 570 pro teins.

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