Corneal scarring from ocular trauma is a major cause of blindness in veterans, active military personnel and civilians affecting 1.5 million Americans each year. Presently, over 167,000 Veterans are legally blind, 1.5 million suffer significantly compromised vision, and >7000 veterans are becoming blind each year. The annual cost for treating blindness in America is $139 billion. Current therapies offer short-term relief, cause multiple side effects and often fails to treat preexisting corneal scars for which corneal transplant surgery is a standard of care. With current funding we have successfully identified potentially the first non-surgical therapy to cure pre-existing corneal scars in vivo, uncovered epigenetic mechanisms regulating corneal fibrosis, established novel single and 2-gene therapies to block myofibroblast formation, characterized novel TGF? DNA-binding proteins, developed a canine in vivo corneal fibrosis model, and identified many newer molecular targets, genes, and drugs to control corneal fibrosis or thinning as evident from 22 publications. Our central hypothesis is that nanoparticle-mediated gene therapy offers long-term relief from corneal blindness without significant side effects and long-term goal remains the development of innovative bench- to-bedside translational nanomedicine approaches to cure pre- and post-corneal scarring in vivo. This project tests 5 novel hypotheses formulated into 3 independent aims: 1) Tests the hypothesis that PEI2- GNPs-mediated Id3 gene (Inhibitor of differentiation) delivery into rabbit stroma will limit transdifferentiation of stromal fibroblast to myofibroblast (a key mechanism causing undesirable wound healing and fibrosis) in the cornea in vivo by disrupting the binding of E-proteins to the promoter of ?-smooth muscle actin (TGF? downstream target gene). 2) Tests 2 hypotheses that (a) PEI2-GNPs-delivered localized HGF+BMP7 gene therapy eliminates preexisting corneal scarring in vivo via mechanisms in which HGF eradicates corneal scarring by selective apoptosis in myofibroblasts and BMP7 prevents re-emergence of new wound healing due to death of established myofibroblasts by counterbalancing profibrotic Smads and (b) HGF+BMP7 delivery into stroma does not compromise characteristic collagen fibrillogenesis required for corneal clarity, maintains normal corneal homeostasis, and is safe to the eye in vivo. 3) Tests 2 novel hypotheses (a) stromal fibroblast differentiation to myofibroblast proceeds via ?-smooth muscle actin (TGF?1 downstream target gene) and is tightly controlled by the co-repressor (5'-TG-3'-interacting factor (TGIF)1, TGIF2, and SnoN) and co-activator (CBP and p300), and (b) the transdifferentiation process can be arrested by the over-expression of identified co-repressor or silencing of co-activator efficiently in vivo in a rabbit model. Successful completion of the proposed research fills critical knowledge gaps and significantly improve our understanding of molecular mechanisms regulating corneal wound healing, lead development of novel nanomedicine approaches for corneal blindness and significantly advances the fibrosis research field.
Relevance to Veterans Health Presently, over 167,000 Veterans are legally blind, 1.5 million have significantly compromised vision, and >7000 veterans becoming blind each year. Corneal scarring is a major cause of blindness among veterans, active military personnel and civilians affecting 1.5 million Americans each year. The research proposed in the project will lead mechanism-based nanomedicine development to precisely control active wound healing in vivo, advance translation of the first non-surgical therapy for preexisting corneal fibrosis towards human clinical trials and identify novel therapeutic targets and strategies for treating, preventing and curing corneal blindness. The successful completion of project fulfills the mission of the Veterans Health Administration to achieve excellence in health care research and offer state-of-the art medical care to our veterans.
|Marlo, Todd L; Giuliano, Elizabeth A; Tripathi, Ratnakar et al. (2018) Altering equine corneal fibroblast differentiation through Smad gene transfer. Vet Ophthalmol 21:132-139|
|Anumanthan, Govindaraj; Gupta, Suneel; Fink, Michael K et al. (2018) KCa3.1 ion channel: A novel therapeutic target for corneal fibrosis. PLoS One 13:e0192145|
|Chaurasia, Shyam S; Lim, Rayne R; Parikh, Bhav H et al. (2018) The NLRP3 Inflammasome May Contribute to Pathologic Neovascularization in the Advanced Stages of Diabetic Retinopathy. Sci Rep 8:2847|
|Marlo, Todd L; Giuliano, Elizabeth A; Sharma, Ajay et al. (2017) Development of a novel ex vivo equine corneal model. Vet Ophthalmol 20:288-293|
|Gronkiewicz, Kristina M; Giuliano, Elizabeth A; Sharma, Ajay et al. (2016) Molecular mechanisms of suberoylanilide hydroxamic acid in the inhibition of TGF-?1-mediated canine corneal fibrosis. Vet Ophthalmol 19:480-487|
|Mohan, Rajiv R; Morgan, Brandie R; Anumanthan, Govindaraj et al. (2016) Characterization of Inhibitor of differentiation (Id) proteins in human cornea. Exp Eye Res 146:145-53|
|Gronkiewicz, K M; Giuliano, E A; Kuroki, K et al. (2016) Development of a novel in vivo corneal fibrosis model in the dog. Exp Eye Res 143:75-88|
|Sharma, Ajay; Anumanthan, Govindaraj; Reyes, Marcos et al. (2016) Epigenetic Modification Prevents Excessive Wound Healing and Scar Formation After Glaucoma Filtration Surgery. Invest Ophthalmol Vis Sci 57:3381-9|
|Lim, Rayne R; Tan, Alison; Liu, Yu-Chi et al. (2016) ITF2357 transactivates Id3 and regulate TGF?/BMP7 signaling pathways to attenuate corneal fibrosis. Sci Rep 6:20841|
|Chaurasia, Shyam S; Lim, Rayne R; Lakshminarayanan, Rajamani et al. (2015) Nanomedicine approaches for corneal diseases. J Funct Biomater 6:277-98|
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