Professor, Department of Cell Biology
Edith Kinney Gaylord Presidential Professor
Adjunct Professor of the Oklahoma Center for Neuroscience
Ph.D., Biochemistry/Cell Biology, Baylor College of Medicine, Houston, Texas
Dr. Naash earned her Masters and Ph.D. in Biochemistry, the latter from Baylor College of Medicine. Her post-doctoral fellowship was in the Department of Ophthalmology at Baylor College of Medicine in Houston. She holds the Edith Kinney Gaylord Presidential Professorship in the Department of Cell Biology and is a former Director of the Cell Biology Graduate Program at OUHSC. She also holds an Adjunct Faculty appointment in the Oklahoma Center for Neuroscience and the OUHSC Graduate College. She is very well published and serves as a reviewer for study sections and journals. She currently serves on study sections for the NIH and the Foundation Fighting Blindness. Dr. Naash is currently funded by three R01 grants from the NIH/NEI, in addition to having funding from the OCAST, OCASCR and the Foundation Fighting Blindness.
1. Photoreceptor-specific tetraspanin proteins in outer segment morphogenesis. There are several ongoing research interests of my group. One of our main interests is to understand the role of photoreceptor tetraspanin proteins [retinal degeneration slow (RDS) and rod outer segment membrane protein-1 (ROM-1] in the morphogenesis of the closed rim structures characteristic of rods in contrast to the open rim structures of cones. This work has been funded by NIH since 1992. We are interested in identifying RDS partners which contribute to the differential role of RDS in maintaining the outer segment (OS) structure in rods vs. cones. Of particular interest are understanding the pathological mechanisms that underlie RDS-associated retinal dystrophies. Without RDS, OSs are not formed, and over 100 different mutations in patients have been linked to several forms of inherited retinal diseases. Proteomics, molecular biology, protein biochemistry, tissue culture, transgenics, knockout and knockin technologies are employed. We are also investigating the effect of disease-causing mutations on RDS/ROM-1 complex formation and studying the processes that result in their targeting to the OS.
2. Nanoparticle-mediated ocular gene delivery and vector engineering. Our second interest is to develop gene and stem cell therapies for eye disease, particularly diseases of the retina and retinal pigment epithelium (RPE). The work is funded by two R01 grants from NIH to develop non-viral therapeutic interventions to combat loss of vision in models of ocular diseases. The eye is outstandingly well suited for the development of novel therapeutic approaches. It is easily accessible and allows local application of therapeutic agents with reduced risk of systemic effects. We are using self-compacted DNA nanotechnology along with advanced vector engineering stragetgies to enhance gene expression levels and longevity of expression. We are testing mini-circle vectors that lack bacterial backbone, self-replicating vectors, and several elements designed to prolong/improve expression, including S/MAR sequences, enhancers, insulators, and helper-independent Sleeping Beauty Trasposon-Transposase. Nanoparticles (NPs) carrying these vectors are designed to deliver therapeutic genes specifically to the RPE or photoreceptors. Historically, non-viral gene delivery options have been plagued by inefficient cellular uptake, silencing of gene expression, and occasionally induction of immune responses. However, we have shown that our NPs are highly efficient in transfecting differentiated, post-mitotic cells and that they exhibit no signs of toxicity, even after repeated dosing to the eye. We also show that these NPs drive long-term gene expression, and can mediate significant improvement in the retinal degenerative phenotype in several models of retinitis pigmentosa, Stargardt’s Macular Dystrophy and Leber’s Congenital Amaurosis (LCA). A key distinguishing feature of these NPs is their large capacity and demonstrated comparable gene expression regardless of vector size (tested up to 20kb). We have also demonstrated that NPs can drive retinal gene expression at levels on a scale comparable to AAVs. Combined, these features make NPs an attractive option for the treatment of chronic monogenic ocular diseases.
3. Adult stem cell therapy for photoreceptors. Cell transplantation represents a promising therapeutic avenue to combat neurodegenerative diseases. Ocular diseases such as age related macular degeneration (AMD) and retinitis pigmentosa (RP) are prime candidates for such therapies. These diseases are characterized by photoreceptor degeneration, and transplanted cells would have to be delivered precisely to the location where the degeneration is observed. Although transplanted embryonic stem cells (ESCs) have been shown to effectively differentiate and integrate into various layers of the retina; it has been repeatedly demonstrated that they fail to differentiate into photoreceptor cells when transplanted into the adult retina. In contrast, it has been shown that post-mitotic retinal progenitor cells (RPCs) extracted from post-natal mice were able to integrate into the outer nuclear layer (ONL) and mature into photoreceptors. This has led us to ask, at what time point in development are cells primed to have neuro-regenerative capability? If the time point/condition at which cells have maximal capacity for integration and differentiation can be determined, then steps can be taken to induce such a condition in vitro, prior to transplantation, with the goal of generating a renewable cell population capable of efficient integration and differentiation. We propose to transplant e-GFP labeled RPCs into wild-type and mouse models of rod and cone degeneration. We plan to track the localization, integration and differentiation of these cells in the host retina and examine retinal structure and function to detect improved phenotypes. We also focused on maximizing integration of RPCs and evaluating the importance of the outer limiting membrane in this process.
Stuck MW, Conley M, Naash, MI (2014) The Y141C knockin mutation in RDS leads to complex phenotypes in the mouse. Hum Mol Genet. 2014 Jul 7. pii: ddu345. [Epub ahead of print].
Mitra RN, Merwin MJ, Han Z, Conley SM, Al-Ubaidi MR, Naash MI. (2014) Nanothrapy induced neuroprotection of photoreceptor cells against oxidative stress in vivo. Free Radic Biol Med. 2014 Jul 24;75C:140-148.
Chakraborty, D., Conley, S. and Naash MI. (2014) Rhodopsin-independent trafficking pathway of RDS and its role in rod outer segment morphogenesis. PLoS One. 2014 Jun 4;9(6):e98939.
Conley SM, Al-Ubaidi MR, Han Z and Naash MI. (2014) Rim formation is not a prerequisite for distribution of cone photoreceptor outer segment proteins. FASEB J. 2014 Aug;28(8):3468-79.
Conley SM, Stuck M, Burnett J, Chakraborty D, Azadi S, Fliesler SJ and Naash MI. (2014) Insights into the mechanisms of macular degeneration associated with the R172W mutation in RDS. Hum Mol Genet. 2014 Jun 15;23(12):3102-14.
Kanan Y, Brobst D, Westmuckett AD, Moore KL, Han Z, Naash MI, and Al-Ubaidi (2014) Fibulin 2, a tyrosine o-sulfated protein, is up-regulated following retinal detachment. J Biol Chem. 2014 May 9;289(19):13419-33.
Mitra RN, Conley SM, Naash MI. (2014) Synthesis and characterization of glycol chitosan mediated DNA nanoparticles for gene delivery to the retinal pigment epithelium. ChemMedChem. 9(1):189-96.
Koirala A, Conley S, Makkia R, Liu Z, Cooper MJ, Sparrow J and Naash MI. (2013) Persistence of non-viral vector mediated RPE65 expression: case for viability as a gene transfer therapy for RPE-based diseases. Journal of Controlled Release. 172(3):745-52. PMCID: PMC3858392.
Koirala A, Makkia R, Conley S, Cooper MJ, and Naash MI (2013) S/MAR-containing DNA nanoparticles promote persistent RPE gene expression and improvement in RPE65-associated LCA. Human Molecular Genetics. 22(8):1632-42. PMCID: PMC360583.
Han Z, Conley S, Makkia R, Cooper MJ, and Naash MI (2012) DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice. J Clin Invest. 122(9):3221-6. PMCID: PMC3428101
University of Oklahoma Health Sciences Center
Department of Cell Biology
940 Stanton L. Young Blvd.
Oklahoma City, OK 73104
Phone: (405) 271-8001 ext. 47969
Fax: (405) 271-3548