Xi-Qin Ding

xi-qin-dingAssociate Professor, Department of Cell Biology
Joanne I. Moore Professorship in Pharmacology

EDUCATION

Ph.D., Lund University, Lund, Sweden

MEMBERSHIPS

Association for Research in Vision and Ophthalmology (ARVO)
International Society for Eye Research (ISER)
​Association for Ocular Pharmacology and Therapeutics (AOPT)


RESEARCH SUMMARY

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. 

 

SELECTED PUBLICATIONS   

Michael R. Butler, Hongwei Ma, Fan Yang, Joshua Belcher, Yun-Zheng Le, Martin Biel, Stylianos Michalakis, Anthony Iuso, David Krizaj, and Xi-Qin Ding. Endoplasmic reticulum (ER) Ca2+-channel activity contributes to ER stress and cone death in cyclic nucleotide-gated channel deficiency. J Biol Chem 2017 May 11, Epub ahead of print.

Hongwei Ma, Fan Yang, Michael R. Butler, Joshua Belcher, T. Michael Redmond, Andrew T. Placzek, Thomas S. Scanlan, and Xi-Qin Ding. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. The FASEB Journal 2017 Apr 20, Epub ahead of print.

Fan Yang, Hongwei Ma, Joshua Belcher, Michael R. Butler, T. Michael Redmond, Sanford L. Boye, William W. Hauswirth, and Xi-Qin Ding. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. The FASEB Journal 30: 4313-4325, 2016. PMCID: PMC5102114.

Xi-Qin Ding, Arjun Thapa, Hongwei Ma, Jianhua Xu, Michael H. Elliott, Karla K. Rodgers, Marci L. Smith, Jin-Shan Wang, Steven J. Pittler, and Vladimir J. Kefalov. 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. PMCID: PMC4861441.

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

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.

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.



 
MAILING ADDRESS

University of Oklahoma Health Sciences Center
Department of Cell Biology
975 NE 10th St.
Oklahoma City, OK 73104
Phone: (405) 271-8001 ext. 47966
Fax: (405) 271-3548

Xi-Qin-Ding@ouhsc.edu