Grant: Project Grant

Depression is a psychiatric condition that places a serious economic and emotional burden on patients, families and society. Its cause remains unknown. Current antidepressants have some degree of treatment efficacy, but also generate numerous side effects. In addition approximately 30% of patients respond poorly to these medications. Therefore, better comprehending the origin and pathological process of depression, and developing drugs that act directly on the disease mechanism, is critical to more effective treatment with fewer side effects. Recent studies show that depression is a progressive disease involving brain cells affected by oxidative stress and inflammation damage. The thioredoxin-interacting protein (Txnip) promotes oxidative stress and inflammation-induced damage. Recently we found that levels of this protein were increased in neurons of mice under chronic stress conditions. Because stress is a major risk factor for depression, our finding suggests that Txnip may contribute to depression. We will study the role of Txnip in chronic stress-induced oxidative stress and inflammation. Our goal is to determine if inhibiting Txnip is a useful strategy for depression treatment. First, we will determine if increasing Txnip in depression accelerates oxidative stress and inflammation. Second, we will block Txnip gene expression in brain in an animal model for depression, and determine if reduction of Txnip can inhibit depressive-like behaviours. This research will use molecular biology and molecular pharmacology techniques on an animal model for depression and on cultured animal brain cells. The work should determine if upregulation of Txnip is important in the pathological process of depression, and if inhibition of Txnip can be used to treat depression. The outcome of this study will lead to identifying compounds that target Txnip, and subsequently clinical trials of new and more effective therapies for depression.