The magnitude of this 570 protein interactome is likely to be due

The magnitude of this 570 protein interactome is likely to be due in part to some high connectivity proteins such as the AKT gene group, which regulate many pathways. The 570 proteins from this interactome were imported into Metacore to query human diseases significantly associated with the mTOR pathway interactome. Significantly associated human diseases likely to be perturbed by mTOR pathway dysfunction were identified using the functional enrichment category within Metacore that relies on curated human disease specific networks. Human lupus and genes of the mTOR pathway interactome Various cancer and non cancer human diseases were identi fied as being significantly associated with the mTOR pathway interactome.
A few cancers, such as selleck inhibitor ovarian neoplasm and pancreatic neoplasm, topped the list of associated diseases, and remarkably these were followed by lupus with significance of association p value of about E 8. 5. Other non cancer dis eases that showed a less significant association are diabetes, obesity, Alzheimers disease, multiple sclerosis and arthritis, all having an association of p 0. 01. Notably, the p values for the other pro inflammation diseases were much less significant than those for lupus. For example, p values for both multiple sclerosis and arthritis are about 1E 3. The genes in the mTOR pathway interactome that are associ ated with lupus are, in large part, distinct from the genes involved in the other non cancer diseases. This is evident from the top scoring Gene Ontology cellular processes for each of these diseases.
For example, in Metacore, selleck the top scoring Gene Ontology cellular processes for lupus are related to apoptosis and cell death, while those for diabetes are related to carbohydrate metabolism, and those for obesity are related to fat metabolism. Both diabetes and obesity show a much more significant association with the mTOR interactome than any pro inflammatory disease other than lupus. Discussion NZBW mice develop nephritis closely resembling that seen in human patients with lupus nephritis. Here we show that an eight week course of 5 mgkg sirolimus delivered three times a week starting at disease onset and contin uing for eight weeks markedly reduced symptoms of disease as measured by proteinuria, kidney histopathology and sur vival. By 52 weeks of age all treated mice were alive despite cessation of treatment many weeks earlier.
Both results described here and previously reported studies, establish that sirolimus treatment prevents progression of autoimmune nephritis and prolongs survival in NZBW mice. A comparable effect of sirolimus treatment has been observed in MRLlpr mice, a second model of lupus and lupus nephritis. We identified genes expressed at abnormal levels in NZBW kidneys by comparing RNA levels in asymptomatic young mice and older mice with symptoms of lupus nephritis.

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