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Our research on proteomics mainly focused on the major depressive disorder, also including other mental illness, such as bipolar disorder and Schizophrenia. The main purpose is to identify disease-specific biomarker for the diagnosis of MDD and explore pathophysiology involved in the disease. The Object of study include human, rat, mouse, Macaca monkeys and Borna disease virus. The samples collected include blood, serum, brain tissue, cerebrospinal fluid, urine, synaptic and cells. Ultimately, The analysis was mainly conducted by quantitative proteomic approach based on two-dimensional gel electrophoresis (2-DE) and isobaric tags for relative and absolute quantitation (iTRAQ). In our study, several altered proteins were found in the plasma sampled from major depressive patients. Most of the differentially expressed proteins are associated with lipid metabolism and immunoregulation, suggesting that the early perturbation of lipid metabolism and immunoregulation may be involved in the pathophysiology of MDD. After validation, one protein were identified the reliable and disease-specific biomarker for the diagnosis of MDD. Our current research is on the pathophisiology mechanism research of the protein in MDD involving intracellular signal transduction pathway.