Brain specific modulation of thyroid hormone levels

A large body of anecdotal observations, clinical studies, and preclinical data suggest that depression may, at times, arise directly due to decreases in thyroid hormone (TH)-dependent signaling within the brain or, at least, can be treated by increasing brain TH. Furthermore, our transcriptomic analyses of human brains over aging indicate an age-dependent state of low TH-signaling in the brain, with the degree of suppression correlating to transcriptional signature of synapse loss, suggesting that manipulating TH levels in the brain may be particularly potent in the elderly - patient population that is difficult to treat with anti-depressants. 

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. We propose to develop a screening platform to search for molecules that modulate the activity of these two targets.