ABSTRACT Photoreceptors degenerate in numerous retinal diseases, including retinitis pigmentosa, Leber congenital amaurosis, and age-related macular degeneration (AMD). The progressive death of cone photoreceptors ultimately leads to vision impairment and blindness. Thyroid hormone (TH) regulates cell proliferation, differentiation, and metabolism. In the retina, TH regulates retinal development and cone opsin expression, and is associated with cone photoreceptor viability. Using mouse models of cone degeneration, we have shown that suppression of TH signaling with anti-thyroid drug treatment or by targeting intracellular TH components iodothyronine deiodinases and thyroid hormone receptor protects cones, whereas stimulation of TH signaling deteriorates cones. The overall objectives of this project are to determine whether TH signaling activity is elevated in degenerating cones/retinas; explore how TH signaling induces cone death, which is essential to understanding how suppressing TH signaling preserves cones; and determine whether suppression of TH signaling in the retina might be an effective strategy for cone protection. Aim 1 will determine whether TH signaling activity is elevated in cone degeneration retinas, including AMD donor eyes. We found that the expression levels of cellular TH components, including the iodothyronine deiodinases and TH receptor, were higher in cone degeneration retinas, suggesting locally elevated TH signaling activity. We will evaluate TH receptor transcriptional activity and TH-regulating genes/pathway activities in cone degeneration retinas, using CUT&RUN-seq technologies and RNA-seq technologies, and assess the effects of TH signaling suppression. Aim 2 will determine whether receptor-interacting serine/threonine-protein kinase (RIPK)/necroptosis signaling contributes to TH-induced cone death. Treatment with triiodothyronine (T3) induced cone death and increased expression of the necroptosis components in the mouse retina, whereas suppressing TH signaling reduced these alterations. We will examine RIPK/necroptosis activity in the mouse retina after TH signaling manipulation. The contribution of RIPK/necroptosis signaling to TH- induced cone death will be evaluated using RIPK inhibitor/genetic deletion. Aim 3 will determine whether changes in mitochondrial metabolism and oxidative stress/damage contribute to TH-induced cone death. Treatment with T3 induced oxidative damage in the retina and increased expression of the mitochondrial metabolism enzymes, whereas suppression of TH signaling reduced these alterations. We will examine mitochondrial metabolism/activity in the retina after TH signaling manipulation and evaluate the effects of antioxidants/metabolic modulators on TH-induced cone death. Completion of the proposed study will help us understand regulation of TH signaling in cone degeneration retinas. This knowledge is essential for the future development of cone protection strategies that act by targeting TH...