Associate Professor, Department of Cell Biology
Joanne I. Moore Professorship of Pharmacology
Ph.D., Lund University, Lund, Sweden
Association for Research in Vision and Ophthalmology (ARVO)International Society for Eye Research (ISER)
Association for Ocular Pharmacology and Therapeutics (AOPT)
We are studying cellular mechanisms and signaling pathways in the retina that are associated with photoreceptor degeneration using mouse models. The objective of our research is to identify novel therapeutic strategies for photoreceptor protection.
Cellular mechanism of cone degeneration in CNG channel deficiency
The cone photoreceptor cyclic nucleotide-gated (CNG) channel is essential for cone phototransduction and cellular calcium homeostasis. Mutations in the channel subunits CNGA3 and CNGB3 account for about 80% of all cases of achromatopsia and are associated with progressive cone dystrophies. Using CNG channel-deficient mouse models, we demonstrated that: 1) cone death in CNG channel deficiency occurs via endoplasmic reticulum (ER) stress-associated apoptosis, 2) CNG channel-deficient retinas display increased activity and expression of the ER calcium channels inositol 1,4,5-trisphosphate receptor and ryanodine receptor, and 3) cellular cGMP level and the cGMP-dependent protein kinase (PKG) activity is dramatically increased and suppressing cGMP/PKG signaling reduces activity of ER calcium channels, ER stress, and cone death. We now focus on the role of ER calcium channel/ER calcium regulation in cone degeneration. Experiments are designed to determine: 1) whether cellular/ER calcium is reduced in CNG channel deficiency, 2) whether suppressing ER calcium channels reduces ER stress and cone death, and 3) whether ER calcium regulation is involved in cGMP/PKG signaling-triggered cone death. We use electrophysiological and biochemical techniques to evaluate cellular/ER calcium levels and ER calcium channel expression/activity in the retina. We apply pharmacological, cellular biological, and molecular biological approaches to suppress ER calcium channels and block cGMP/PKG signaling, including the use of the channel/enzyme blockers, shRNA knockdown, and conditional knockout. Upon completion of this study, we will be able to establish whether targeting ER calcium channels represents a novel strategy for cone preservation in retinal degeneration.
Thyroid hormone signaling and cone photoreceptor viability
Thyroid hormone (TH) signaling regulates cell growth, differentiation, metabolic homeostasis, and cell death. In the retina, TH signaling plays a central role in cone opsin expression. TH signaling also regulates cone photoreceptor viability. Treatment with TH triiodothyronine (T3) causes cone death in mice. This effect is reversed by deletion of the TH receptor (TR) gene. Using mouse models of cone degeneration, we demonstrated that suppressing TH signaling with anti-thyroid drug preserves cones. We currently explore the potential of inhibition of TH signaling locally in the retina to preserve cones. In mammals, the thyroid gland predominantly produces the prohormone thyroxine (T4), along with a small amount of the bioactive hormone T3. The cellular TH signaling in local tissues is highly regulated by the two selenocysteine-containing iodothyronine deiodinases, DIO2, and DIO3. DIO2 converts T4 to T3 whereas DIO3 degrades T3 and T4 to inactive forms. We apply three strategies to suppress TH signaling in the retina: 1) blocking TR using an TR antagonist and TR deletion, 2) reducing cellular level of T3 by overexpression of DIO3, and 3) reducing cellular level of T3 using an DIO2 inhibitor and DIO2 deletion. Upon completion of this study, we will be able to establish whether suppressing TH signaling locally in the retina represents a novel strategy for cone protection in retinal degeneration.
Hongwei Ma, Michael R. Butler, Arjun Thapa, Josh Belcher, Fan Yang, Wolfgang Baehr, Martin Biel, Stylianos Michalakis, and Xi-Qin Ding. cGMP/PKG Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of CNG Channel-Deficient Mice. J Biol Chem. 2015, 290(34):20880-92. PMCID: PMC3365688.
Hongwei Ma, Arjun Thapa, Lynsie Morris, Redmond T. Michael, Wolfgang Baehr, and Xi-Qin Ding. Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration. Proc Natl Acad Sci USA. 2014, 111(9):3602-7. PMCID: PMC3948228.
Jianhua Xu, Lynsie Morris, Arjun Thapa, Hongwei Ma, Stylianos Michalakis, Martin Biel, Wolfgang Baehr, Igor V. Peshenko, Alexander M. Dizhoor, and Xi-Qin Ding. cGMP accumulation causes photoreceptor degeneration in CNG channel deficiency: Evidence of cGMP cytotoxicity independently of enhanced CNG channel function. J Neurosci, 2013, 33(37):14939-14948, PMCID: PMC3771030.
Hongwei Ma, Arjun Thapa, Lynsie Morris, Stylianos Michalakis, Martin Biel, Mark Barton Frank, Melissa Bebak, and Xi-Qin Ding. Loss of cone cyclic nucleotide-gated channel leads to alterations of light response modulating system and cellular stress response pathways: a gene expression profiling study. Hum Mol Genet, 2013, 22(19):3906-3919, PMCID: PMC3766184.
Stylianos Michalakis, Jianhua Xu, Martin Biel, and Xi-Qin Ding. Detection of cGMP in the Degenerating Retina, Methods in Molecular Biology, 2013, 1020:235-45.
Arjun Thapa, Lynsie Morris, Jianhua Xu, Hongwei Ma, Stylianos Michalakis, Martin Biel and Xi-Qin Ding. Endoplasmic Reticulum Stress-associated Cone Photoreceptor Degeneration in Cyclic Nucleotide-gated Channel Deficiency. J Biol Chem. 2012, 287(22):18018-29. PMCID: PMC3365688.
Jianhua Xu, Lynsie M. Morris, Stylianos Michalakis, Martin Biel, Steven J. Fliesler, David M. Sherry and Xi-Qin Ding. CNGA3 Deficiency Affects Cone Synaptic Terminal Structure and Function and Leads to Secondary Rod Dysfunction and Degeneration. Invest Ophthalmol. Vis. Sci. 2012, 53:1117-29. PMCID: PMC3339899.
Livia S Carvalho, Jianhua Xu, Rachael A Pearson, Alexander J Smith, James W Bainbridge, Lynsie M Morris, Steven J Fliesler, Xi-Qin Ding and Robin R Ali. Long-term and Age-dependent Restoration of Visual Function in A Mouse Model of CNGB3-associated Achromatopsia following Gene Therapy. Human Molecular Genetics 2011, 20(16):3161-75. PMCID: PMC3140821.
Alexander V. Matveev, J. Browning Fitzgerald, Jianhua Xu, Anna P. Malykhina, Karla K. Rodgers, and Xi-Qin Ding. The Disease-Causing Mutations in the Carboxyl-Terminus of Cone Cyclic Nucleotide-Gated Channel CNGA3 Subunit Alter the Local Secondary Structure and Interfere with the Channel Active Conformational Change. Biochemistry, 2010, 49(8):1628-39. PMCID: PMC2829136.
Xi-Qin Ding, Cynthia S. Harry, Umino Y, Alexander V. Matveev, Steven J. Fliesler and Robert B. Barlow. Impaired Cone Function and Cone Degeneration Resulting from CNGB3 Deficiency: Down-regulation of CNGA3 Biosynthesis as a Potential Mechanism. Human Molecular Genetics 2009, 18(24):4770-4780. PMCID: PMC2778372.
University of Oklahoma Health Sciences Center
Department of Cell Biology
940 Stanton L Young Blvd., BMS 553
Oklahoma City, OK 73104
Phone: (405) 271-8001 ext. 47966
Fax: (405) 271-3548