Discovery and optimization of thyroid hormone modulating molecules

Many lines of data suggest that depression may, at times, arise from decreased brain thyroid hormone (TH) signaling or be treated by increasing brain TH. Furthermore, our transcriptomic analyses of aging human brains indicate an age-dependent state of low TH-signaling in the brain, with the degree of suppression correlating to transcriptional signatures of synapse loss. Thus, manipulating brain TH levels may alleviate depression, particularly in the elderly, who are difficult to treat with antidepressants. Unfortunately, increasing peripheral TH is relatively ineffective at manipulating brain TH and has serious side effects on the heart and bone. Our studies identified at least two potential brain enriched targets whose activity can be manipulated to increase TH activity in the brain and thereby treat depression. In a previous QFASTR pilot award, we developed a screening platform to search for molecules that modulate the activity of these two targets. We now propose to exploit this platform to screen for and then optimize molecules.