This suggests a close functional association of mTOR pathway with disease mechanisms. In the context of the findings reported here, it is worth noting that steroid and cyclophosphamide, known to ameliorate lupus, directly impact some components of the mTOR pathway. In additional to preventing nephritis, sirolimus also had striking effects on the anti DNA antibody titres in mice with lupus, so we addressed the connectivity of genes linked to any form of lupus with the mTOR pathway. About 50% of the lupus genes curated as lupus disease genes from human and rodent species in Ingenuity and MetaCore can be linked to the rapalog mTOR pathway. The connectivity would, no doubt have been higher with the use of automatically extracted rela tionships from the biomedical literature.
selelck kinase inhibitor However, the algo rithms used in automatic extractions cannot approximate human reasoning and return a mixture of true and false posi tives. Therefore, we relied exclusively on manually curated databases of protein findings and our results should be viewed as a lower estimate of connectivity. To assess the significance of the association between human lupus genes and the mTOR pathway, we built an mTOR path way interactome using IPA. We then queried which human disease networks in Meta core were best represented in the mTOR pathway interac tome. Of the 87 human disease networks represented in Metacore, human lupus was identified as being highly signifi cant, with only two cancers showing more significant associa tions.
Additional cancer and non cancer diseases were also identified through this process, including Alzheimers disease and other autoimmune diseases such as multiple sclerosis and arthritis. Indeed recent work has uncovered a strong link between the mTOR pathway, Treg function and autoimmunity. kinase inhibitor PH-797804 Rapamycin was shown to inhibit AKT mediated repression of FOXP3. FOXP3 is a critical player in Treg cell differentiation and maintenance and defi ciency of FOXP3 in both humans and mice is associated with multi organ autoimmunity and lymphoproliferative disorders. Having investigated the human disease mTOR pathway con nectivity, we then widened our analysis by exploring the validity of the claim of connectivity by searching the literature for data showing the effects on rapalogs on these human diseases. By conducting these analyses independently of Metacore, we confirmed the relationship between the mTOR pathway and some human diseases, such as multiple sclerosis, dia betes, arthritis and some cancers. A search of the clinical trial database reports ongoing clini cal studies with rapalogs in a number of these diseases, and the analyses we present here support such studies.