Bio-molecular Network-Based Study On Lipid Raft And TRAIL Signaling Pathway

Molecules in the cells seldom function independently, but work cooperatively withother molecules in the same cell, other cells and even other tissues. So it is quiteimportant to use biological molecular network to study biological problems. Basing onthe network, we can study multiple molecules simultaneously and systematically tounveil the mechanisms underlying biological phenomena. Recently, a lot ofbio-molecular networks have been developed to study biological problems. Thescientists have high hopes for applying bio-molecular network to pathology study,disease diagnosis and treatment. In this paper, based on bio-molecular network andsystem biology analysis, we studied two important biological problems, the lipid raft inthe cell membrane and TRAIL induced apoptosis pathway.The first part is a study on the function of lipid raft basing on the protein-proteininteraction network analysis. We collected the first lipid raft protein dataset. Accordingto the dataset, we annotated the localization of proteins in the human protein-proteininteraction network. By analyzing the annotated network, we found that the lipid raftproteins are central, act as bottlenecks and manage the interaction of different modulesin the network. The protein-protein interactions they involved in are essential for theconnectivity and stability of the network. Besides the lipid raft proteins, we alsointroduced an index called "lipid raft dependency"(LRD) to measure the correlation oflipid raft and all proteins. We found that the high-LRD proteins have specific biologicalfunctions and are usually coded by essential genes and disease genes. This indicatedthat lipid raft may be associated with tissue development and pathological processes. Bystudying the LRD of disease genes, we predicted14diseases related to lipid raft, suchas malaria. From the further analysis, we found that lipid raft regulated the pathologicalprocesses through specific biological processes and pathways. By calculating the LRDof expressed genes in79human tissues and cell lines, we also found that the function oflipid raft has tissue specificity.The second part of the paper is a study of the regulation mechanism of TRAILinduced apoptosis pathway by signaling network analysis. By using ordinary differentialequations, we simulated the signal transduction of TRAIL pathway and identified the key components and reactions in the pathway. By modeling the binding of TRAILreceptors and ligands, we checked the two controversial models of inhibition ofapoptosis by decoy receptors. We verified that the decoy receptor binds the deathreceptor by pre-ligand binding domain and inhibit apoptosis. Moreover, by modelingthe downstream of the pathway, we found that the apoptosis signal is amplified and themodulators inhibit apoptosis to some extent. We also found that the modulators can beinhibited by the feedback loop.