Academic Title
Associate Professor
Contact Information
(352) 273-7548 (phone)
(352) 392-0573 (fax)
astra@ufl.edu
Lab
R1-236
About
Dr. Dinculescu received her Ph.D. in Biochemistry from University of Florida in 2002. Her main research focus is on developing therapeutic approaches for Usher syndrome type III (USH3A), an autosomal recessive disorder caused by mutations in Clarin-1 (CLRN1) gene, leading to progressive retinal degeneration and hearing loss. In addition, she studies the pathological processes affecting the neural retina/retinal pigment epithelium (RPE)/Bruch’s membrane interface, and the mechanisms leading to the formation of drusen in age-related macular degeneration. She developed an interest in complement C1q tumor necrosis factor-related protein-5 (C1QTNF5) following her discovery that mutant S163R C1QTNF5 forms globular aggregates in the RPE, and accumulates as thick, widespread, extracellular RPE basal laminar deposits. She is currently testing various approaches aimed at preventing the abnormal protein aggregation in RPE, by modulating chaperone expression and targeting the autophagy pathway.
Areas of Interest
- inherited retinal diseases
- Usher syndrome
- Age-related macular degeneration (AMD)
- recombinant AAV-mediated gene therapy
- protein aggregation
- retinal pigment epithelium
- extracellular matrix remodeling
Grants
R01 EY026559-01A1, Astra Dinculescu (PI) 09/01/2016-08/31/2021
“Clarin-1 retinal function and therapeutic implications for USH3”
M2017035 BrightFocus Foundation Award, Astra Dinculescu (PI) 06/01/2017-05/01/2019
“The role of basal C1QTNF5-S163R mutant deposits in drusen formation: implications for Age Related Macular Degeneration”
Publications
Xu L, Bolch SN, Santiago CP, Dyka FM, Akil O, Lobanova ES, Wang Y, Martemyanov KA, Hauswirth WW, Smith WC, Handa JT, Blackshaw S, Ash JD, Dinculescu A. Clarin-1 expression in adult mouse and human retina highlights a role of Müller glia in Usher syndrome. J Pathol. 2019 Oct 18;. doi: 10.1002/path.5360. PubMed PMID: 31625146.
Dinculescu A, Dyka FM, Min SH, Stupay RM, Hooper MJ, Smith WC, Hauswirth WW. Co-Expression of Wild-Type and Mutant S163R C1QTNF5 in Retinal Pigment Epithelium. Adv Exp Med Biol. 2018;1074:61-6. doi: 10.1007/978-3-319-75402-4_8. PubMed PMID: 29721928.
Deng WT, Kolandaivelu S, Dinculescu A, Li J, Zhu P, Chiodo VA, Ramamurthy V, Hauswirth WW. Cone Phosphodiesterase-6gamma’ Subunit Augments Cone PDE6 Holoenzyme Assembly and Stability in a Mouse Model Lacking Both Rod and Cone PDE6 Catalytic Subunits. Front Mol Neurosci. 2018;11:233. doi: 10.3389/fnmol.2018.00233. PubMed PMID: 30038560; PMCID: PMC6046437.
Chekuri A, Sahu B, Chavali VRM, Voronchikhina M, Hermida AS, Suk JJ, Alapati AN, Bartsch DU, Ayala-Ramirez R, Zenteno JC, Dinculescu A, Jablonski MM, Borooah S, Ayyagari R. The long-term effects of gene therapy in a novel mouse model of human MFRP-associated retinopathy. Hum Gene Ther. 2018. doi: 10.1089/hum.2018.192. PubMed PMID: 30499344.
Mowat FM, Occelli LM, Bartoe JT, Gervais KJ, Bruewer AR, Querubin J, Dinculescu A, Boye SL, Hauswirth WW, Petersen-Jones SM. Gene Therapy in a Large Animal Model of PDE6A-Retinitis Pigmentosa. Front Neurosci. 2017;11:342. doi: 10.3389/fnins.2017.00342. PubMed PMID: 28676737; PMCID: PMC5476745.
Geng R, Omar A, Gopal SR, Chen DH, Stepanyan R, Basch ML, Dinculescu A, Furness DN, Saperstein D, Hauswirth W, Lustig LR, Alagramam KN. Modeling and Preventing Progressive Hearing Loss in Usher Syndrome III. Sci Rep. 2017;7(1):13480. doi: 10.1038/s41598-017-13620-9. PubMed PMID: 29044151; PMCID: PMC5647385.
Dinculescu A, Stupay RM, Deng WT, Dyka FM, Min SH, Boye SL, Chiodo VA, Abrahan CE, Zhu P, Li Q, Strettoi E, Novelli E, Nagel-Wolfrum K, Wolfrum U, Smith WC, Hauswirth WW. AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy. PLoS One. 2016;11(2):e0148874. doi: 10.1371/journal.pone.0148874. PubMed PMID: 26881841; PMCID: PMC4755610.
Dinculescu A, Min SH, Dyka FM, Deng WT, Stupay RM, Chiodo V, Smith WC, Hauswirth WW. Pathological Effects of Mutant C1QTNF5 (S163R) Expression in Murine Retinal Pigment Epithelium. Invest Ophthalmol Vis Sci. 2015;56(11):6971-80. doi: 10.1167/iovs.15-17166. PubMed PMID: 26513502; PMCID: PMC4627469.
Deng WT, Dyka FM, Dinculescu A, Li J, Zhu P, Chiodo VA, Boye SL, Conlon TJ, Erger K, Cossette T, Hauswirth WW. Stability and Safety of an AAV Vector for Treating RPGR-ORF15 X-Linked Retinitis Pigmentosa. Hum Gene Ther. 2015;26(9):593-602. doi: 10.1089/hum.2015.035. PubMed PMID: 26076799; PMCID: PMC4575541.
Mowat FM, Gornik KR, Dinculescu A, Boye SL, Hauswirth WW, Petersen-Jones SM, Bartoe JT. Tyrosine capsid-mutant AAV vectors for gene delivery to the canine retina from a subretinal or intravitreal approach. Gene Ther. 2014;21(1):96-105. doi: 10.1038/gt.2013.64. PubMed PMID: 24225638; PMCID: PMC3880610.
Dinculescu A, Min SH, Deng WT, Li Q, Hauswirth WW. Gene therapy in the rd6 mouse model of retinal degeneration. Adv Exp Med Biol. 2014;801:711-8. doi: 10.1007/978-1-4614-3209-8_89. PubMed PMID: 24664762.
Han J, Dinculescu A, Dai X, Du W, Smith WC, Pang J. Review: the history and role of naturally occurring mouse models with Pde6b mutations. Mol Vis. 2013;19:2579-89. PubMed PMID: 24367157; PMCID: PMC3869645.
Deng WT, Sakurai K, Kolandaivelu S, Kolesnikov AV, Dinculescu A, Li J, Zhu P, Liu X, Pang J, Chiodo VA, Boye SL, Chang B, Ramamurthy V, Kefalov VJ, Hauswirth WW. Cone phosphodiesterase-6alpha’ restores rod function and confers distinct physiological properties in the rod phosphodiesterase-6beta-deficient rd10 mouse. J Neurosci. 2013;33(29):11745-53. doi: 10.1523/JNEUROSCI.1536-13.2013. PubMed PMID: 23864662; PMCID: PMC3713718.
Genetic Cause
USH syndrome represents the most common genetic cause of combined deafness and blindness, with an estimated prevalence ranging from 4 to 17 cases per 100,000 people worldwide. It results in the progressive loss of the retinal photoreceptors in the eye and the auditory hair cells in the inner ear. Photoreceptors are key neurons responsible for converting light-signals into electrical signals that are transmitted to the secondary retinal neurons, and ultimately to the brain. They are strategically located in the outermost layer of the neural retina, protected and nurtured by two major non-neuronal cell types: the retinal pigmented epithelium (RPE) and Müller glia. Research conducted in our laboratory is mainly dedicated to developing therapeutic strategies to prevent vision loss in Usher syndrome type III (USH3), a disorder caused by mutations in the Clarin-1 (CLRN1) gene, leading to progressive hearing loss and retinal degeneration.
The biological function of CLRN1 in the retina is currently not understood. Importantly, there are no therapeutic approaches to prevent vision loss in USH3 patients. A major challenge hindering the development of treatments to stop the photoreceptor cell death in this disorder is the lack of models that mimic the human USH3 vision loss. Therefore, we are currently developing and characterizing novel USH3 models that will contribute greatly to the advancement of our understanding of this disease, as well as our ability to treat it. A second major challenge is the fact that CLRN1 protein is normally present at very low levels in the retina, and remains undetectable with our current immunostaining techniques. By using highly sensitive assays, we have recently demonstrated that CLRN1 is produced by retinal Müller glia in multiple species, including humans, thus establishing a potential target for future gene therapy applications.
Detection of Clarin-1 protein in Müller glia following AAV-mediated gene delivery to the retina
One of the major goals of our laboratory is to develop adeno-associated viral vectors (AAVs) for therapeutic gene delivery to Müller glia, to restore normal CLRN1 expression in the retina. Müller glia are long, tree-shaped cells reaching out from the inner retina and spanning its entire thickness. They are involved in many critical aspects of retinal cell biology, including neuronal development, modulation of neuronal synaptic activity, metabolic and structural support. They are essential for maintaining the normal function and long-term survival of both rod and cone photoreceptors. Ultimately, we seek to understand the roles of CLRN1 protein in Müller glia and how its omission specifically impacts the postnatal and adult retina, in order to develop safe AAV-based gene-therapy tools for preventing blindness in USH3 patients.