Assistant Professor of Research, Department of Cell Biology
Ph.D., University of Southern Mississippi
Understanding the mechanisms of retinal cell protection by suppression of thyroid hormone signaling
Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. In the retina, TH signaling affects cone photoreceptor and retinal pigmented epithelial (RPE) cell viability. We demonstrated that suppressing TH signaling by anti-thyroid drug treatment, targeting iodothyronine deiodinases to reduce cellular triiodothyronine level, or blocking TH receptors preserves cones in mouse models of retinal degeneration. We also observed that suppressing TH signaling protects RPE cells from oxidative stress challenge. We now focus on the mechanisms underlying TH signaling regulation of cone and RPE cell viability. We use biochemical, morphological and genetic approaches to determine the roles of the cell death pathways and mitochondrial function/oxidative stress responses in TH signaling suppression-induced cell protection. Completion of the proposed study will help determine whether suppressing TH signaling locally in the retina represents a therapeutic strategy for photoreceptor and RPE protection.
Understanding the mechanisms of cone degeneration in CNG channel deficiency
The cyclic nucleotide-gated (CNG) channel plays a pivotal role in phototransduction. Mutations in genes encoding the cone CNG channel subunits account for about 80% of all cases of achromatopsia, and are associated with progressive cone dystrophies. We have previously demonstrated that endoplasmic reticulum (ER) stress-associated apoptosis, activation of the ER calcium channels inositol 1,4,5-trisphosphate receptor and ryanodine receptor, and activation of the cGMP-dependent protein kinase (PKG) are associated with cone death in CNG channel deficiency. We now focus on the role of ER calcium channels/ER calcium regulation in ER stress, protein mistrafficking, and cone death. We use biochemical, morphological and genetic approaches to evaluate ER calcium channel expression/activity and cone survival/death in the retina. Upon completion of the proposed study, we will better understand whether targeting ER calcium channels represents a novel strategy for cone preservation.
Office Phone: 405-271-8001 ext. 47950 Fax Number: 405-271-3548
Email: Hongwei-Ma@ouhsc.edu
University of Oklahoma Health Sciences Center Department of Cell Biology 975 NE 10th St., BRC456 Oklahoma City, OK 73104
Association for Research in Vision and Ophthalmology (ARVO) International Society for Eye Research (ISER) Association for Ocular Pharmacology and Therapeutics (AOPT)
Butler MR, Ma H, Yang F, Belcher J, Le YZ, Mikoshiba K, Biel M, Michalakis S, Iuso A, Krizaj D, Ding XQ: Endoplasmic reticulum (ER) Ca2+-channel activity contributes to ER stress and cone death in cyclic nucleotide-gated channel deficiency. J Biol Chem 2017, 292:11189-11205.
Ma H, Yang F, Butler MR, Belcher J, Redmond TM, Placzek AT, Scanlan TS, Ding XQ: Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. FASEB J 2017, 31:3425-3438.
Yang F, Ma H, Belcher J, Butler MR, Redmond TM, Boye SL, Hauswirth WW, Ding XQ: Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. FASEB J 2016, 30:4313-4325.
Ma H, Ding XQ: Thyroid hormone signaling and cone photoreceptor viability. Adv Exp Med Biol 2016, 854:613-618.
Fiskus W, Coothankandaswamy V, Chen J, Ma H, Ha K, Saenz DT, Krieger SS, Mill CP, Sun B, Huang P, et al: SIRT2 deacetylates and inhibits the peroxidase activity of peroxiredoxin-1 to sensitize breast cancer cells to oxidant stress-inducing agents. Cancer Res 2016, 76:5467-5478.
Ding XQ, Thapa A, Ma H, Xu J, Elliott MH, Rodgers KK, Smith ML, Wang JS, Pittler SJ, Kefalov VJ: The B3 subunit of the cone cyclic nucleotide-gated channel regulates the light responses of cones and contributes to the channel structural flexibility. J Biol Chem 2016, 291:8721-8734.
Ma H, Butler MR, Thapa A, Belcher J, Yang F, Baehr W, Biel M, Michalakis S, Ding XQ: cGMP/Protein Kinase G signaling suppresses inositol 1,4,5-trisphosphate receptor phosphorylation and promotes endoplasmic reticulum stress in photoreceptors of cyclic nucleotide-gated channel-deficient mice. J Biol Chem 2015, 290:20880-20892.
Ma H, Thapa A, Morris L, Redmond TM, Baehr W, Ding XQ: Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration. Proc Natl Acad Sci USA 2014, 111:3602-3607.
Xu J, Morris L, Thapa A, Ma H, Michalakis S, Biel M, Baehr W, Peshenko IV, Dizhoor AM, Ding XQ: cGMP accumulation causes photoreceptor degeneration in CNG channel deficiency: evidence of cGMP cytotoxicity independently of enhanced CNG channel function. J Neurosci 2013, 33:14939-14948.
Ma H, Thapa A, Morris LM, Michalakis S, Biel M, Frank MB, Bebak M, Ding XQ: Loss of cone cyclic nucleotide-gated channel leads to alterations in light response modulating system and cellular stress response pathways: a gene expression profiling study. Hum Mol Genet 2013, 22:3906-3919.
Thapa A, Morris L, Xu J, Ma H, Michalakis S, Biel M, Ding XQ: Endoplasmic reticulum stress-associated cone photoreceptor degeneration in cyclic nucleotide-gated channel deficiency. J Biol Chem 2012, 287:18018-18029.
Profile Last Updated: Feb. 23, 2018