Frank M. Dyka

University of Florida

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William W. Hauswirth

University of Florida

Sanford L. Boye

University of Florida

Astra Dinculescu

University of Florida

Vince A. Chiodo

University of Florida

Robert S. Molday

University of British Columbia

W. Clay Smith

University of Florida

Renee C. Ryals

Oregon Health & Science University

Wen‐Tao Deng

Hainan University

Susan Bolch

University of Florida

Seok-Hong Min

University of Florida

Cooperative Institutions

University of Florida

University of British Columbia

Florida College

Harvard University

Smith-Kettlewell Eye Research Institute

National Institutes of Health

Massachusetts Eye and Ear Infirmary

National Institute of Allergy and Infectious Diseases

Ophthalmology Associates (United States)

University of California, San Diego

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A novel epitope-tagged Clarin-1 knock-in mouse with retinal dysfunction and profound congenital deafness

Investigative Ophthalmology & Visual Science (2020)

Astra Dinculescu Omar Akil Susan Bolch Frank M. Dyka William Ruddick

Gene knockin

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Metabotropic glutamate receptors are differentially regulated under elevated intraocular pressure

Journal of Neurochemistry (2004)

Frank M. Dyka Christian Albrecht May Ralf Enz

Abtract Glaucoma is a leading cause of blindness, ultimatively resulting in the apoptotic death of retinal ganglion cells. However, molecular mechanisms involved in ganglion cell death are poorly understood. While the involvement of ionotropic glutamate receptors has been extensively studied, virtually nothing is known about its metabotropic counterparts. Here, we compared the retinal gene expression of metabotropic glutamate receptors (mGluR) in eyes with normal and elevated intraocular pressure (IOP) of DBA/2J mice, a model for secondary angle‐closure glaucoma using RT–PCR and immunohistochemistry. Elevated IOP in DBA/2J mice significantly increased retinal gene expression of mGluR1a, mGluR2, mGluR4a, mGluR4b, mGluR6 and mGluR7a when compared to C57BL/6 control animals, while mGluR5a/b and mGluR8a were decreased and no difference was observed for mGluR3 and mGluR8b. Specific antibodies detected an increase of mGluR1a and mGluR5a/b in both synaptic layers and in the ganglion cell layer of the retina under elevated IOP. Because ganglion cell death in DBA/2J mice occurs most likely by apoptotic mechanisms, we demonstrated up‐regulation of mGluRs in neurons undergoing apoptosis. In summary, we support the idea that the specific gene regulation of mGluRs is a part of the glaucoma‐like pathological process that develops in the eyes of DBA/2J mice.

Inner nuclear layer

10.1111/j.1471-4159.2004.02474.x

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Interaction of X-linked Retinitis Pigmentosa Protein 2 (rp2) With N-ethylmaleimide Sensitive Factor (nsf)

Investigative Ophthalmology & Visual Science (2009)

L. L. Molday Juha M. Holopainen Christiana L. Cheng Gurinder Johal Jonathan A. Coleman

N-Ethylmaleimide

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Phenotypic consequences of amino acid substitutions at the S163 position in C1QTNF5 protein following expression in murine RPE

Investigative Ophthalmology & Visual Science (2018)

Astra Dinculescu Susan Bolch Frank M. Dyka Manoj Kulkarni Chiab P. Simpson

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Dual Adeno-Associated Virus Vector Treatment of Autosomal Recessive Stargardt Disease

Investigative Ophthalmology & Visual Science (2018)

Frank M. Dyka William W. Hauswirth

Stargardt disease

Adeno-associated virus

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Dual Adeno-Associated Virus Vector mediated gene therapy for autosomal recessive Stargardt Disease

Investigative Ophthalmology & Visual Science (2019)

Frank M. Dyka Laurie L. Molday Vince A. Chiodo Robert S. Molday William W. Hauswirth

Adeno-associated virus

Stargardt disease

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Subunits of the epithelial sodium channel family are differentially expressed in the retina of mice with ocular hypertension

Journal of Neurochemistry (2005)

Frank M. Dyka Christian Albrecht May Ralf Enz

Abstract Glaucoma is a prevalent cause of blindness, resulting in the apoptotic death of retinal ganglion cells and optic nerve degeneration. The disease is often associated with elevated intraocular pressure, however, molecular mechanisms involved in ganglion cell death are poorly understood. To identify proteins contributing to this pathological process, we analysed the retinal gene expression of DBA/2J mice that develop an elevated intraocular pressure by the age of 6 months with subsequent ganglion cell loss. In this study, we identified subunits of the epithelial sodium channel (ENaC) family that are specifically expressed under elevated intraocular pressure. Using reverse transcriptase polymerase chain reaction we observed a significant increase of α‐ENaC in the neuronal retina of DBA/2J mice when compared with control animals, while β‐ENaC and γ‐ENaC were not detectable in this tissue. Specific immune sera to ENaC subunits showed up‐regulation of α‐ENaC in synaptic and nuclear layers of the retina, and in the retinal pigment epithelium. Consistent with our polymerase chain reaction data, β‐ENaC was not detected by specific antibodies in the retina, while γ‐ENaC was only present in the retinal pigment epithelium under ocular hypertension. Finally, the increase of α‐ENaC gene expression in the neuronal retina and the retinal pigment epithelium was not observed in other tissues of DBA/2J mice. Since the intraocular pressure is regulated by the transport of aqueous humour across epithelial structures of the eye that in turn is associated with ion flux, the specific up‐regulation of ENaC proteins could serve as a protecting mechanism against elevated intraocular pressure.

Epithelial sodium channel

Ganglion cell layer

10.1111/j.1471-4159.2005.03177.x

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An unusual X-linked retinoschisis phenotype and biochemical characterization of the W112C RS1 mutation

Vision Research (2006)

Alessandro Iannaccone Marco Mura Frank M. Dyka Maria Laura Ciccarelli Beverly M. Yashar

Retinoschisis

Erg

10.1016/j.visres.2006.06.011

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Optimizing rAAV vectors to target ON bipolar cells

Investigative Ophthalmology & Visual Science (2014)

Miranda White Frank M. Dyka Charles N. de Leeuw Seok-Hong Min Qing Ruan

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Targeting Photoreceptors via Intravitreal Delivery Using Novel, Capsid-Mutated AAV Vectors

PLoS ONE (2013)

Christine N. Kay Renee C. Ryals George Aslanidi Seok Hong Min Qing Ruan

Development of viral vectors capable of transducing photoreceptors by less invasive methods than subretinal injection would provide a major advancement in retinal gene therapy. We sought to develop novel AAV vectors optimized for photoreceptor transduction following intravitreal delivery and to develop methodology for quantifying this transduction in vivo. Surface exposed tyrosine (Y) and threonine (T) residues on the capsids of AAV2, AAV5 and AAV8 were changed to phenylalanine (F) and valine (V), respectively. Transduction efficiencies of self-complimentary, capsid-mutant and unmodified AAV vectors containing the smCBA promoter and mCherry cDNA were initially scored in vitro using a cone photoreceptor cell line. Capsid mutants exhibiting the highest transduction efficiencies relative to unmodified vectors were then injected intravitreally into transgenic mice constitutively expressing a Rhodopsin-GFP fusion protein in rod photoreceptors (Rho-GFP mice). Photoreceptor transduction was quantified by fluorescent activated cell sorting (FACS) by counting cells positive for both GFP and mCherry. To explore the utility of the capsid mutants, standard, (non-self-complementary) AAV vectors containing the human rhodopsin kinase promoter (hGRK1) were made. Vectors were intravitreally injected in wildtype mice to assess whether efficient expression exclusive to photoreceptors was achievable. To restrict off-target expression in cells of the inner and middle retina, subsequent vectors incorporated multiple target sequences for miR181, an miRNA endogenously expressed in the inner and middle retina. Results showed that AAV2 containing four Y to F mutations combined with a single T to V mutation (quadY−F+T−V) transduced photoreceptors most efficiently. Robust photoreceptor expression was mediated by AAV2(quadY−F+T−V) −hGRK1−GFP. Observed off-target expression was reduced by incorporating target sequence for a miRNA highly expressed in inner/middle retina, miR181c. Thus we have identified a novel AAV vector capable of transducing photoreceptors following intravitreal delivery to mouse. Furthermore, we describe a robust methodology for quantifying photoreceptor transduction from intravitreally delivered AAV vectors.

10.1371/journal.pone.0062097

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Citations (160)