Visual clarity depends on strict vascular demarcations between ocular vascular beds and vision-critical tissues such as the cornea and macular photoreceptors. Our long-range goals are to elucidate the molecular network that maintains this compartmentalization in the eye and to understand how the network is altered in pathological ocular angiogenesis. Our immediate goal is to dissect tissue-specific differences in vascular versus neuronal requirements for vascular endothelial growth factor (VEGF) under normal and pathological conditions. We will determine how soluble VEGF receptors orchestrate cross-talk among corneal compartments to titrate the balance between VEGF requirements for vascular demarcation and neuronal homeostasis. We will genetically dissect the roles of specific ocular compartments to determine how VEGF-dependent nerve regeneration is accomplished without triggering a vascular breach. We will rigorously analyze the vascular response of soluble VEGFR1 (sFlt1) knockdown within each corneal compartment during epithelial wound healing and nerve regeneration. Complementing this analysis, we will dissect the roles of sVEGF receptors expressed on corneal neurons. Finally, we will elucidate whether splice shifting morpholinos conjugated to a neovessel-targeting peptide motif can treat corneal neovascularization (KNV) and choroidal neovascularization (CNV).
Our specific aims for the next grant period are:
Specific Aim #1 : To rigorously test functional requirements for soluble VEGFR1 (sFlt1) or soluble VEGFR2 (sKDR) within specific corneal compartments for achieving vascular demarcation and appropriate innervation in the normal and injured cornea.
Specific Aim #2 : To determine whether aniridia-associated KNV resulting from Pax6 haploinsufficiency derives from neural crest related defects in the corneal stroma that shift angiogenic potential, and whether vascular breach from limbal stem cell deficiency is a secondary paracrine mechanism due to epithelial upregulation of MT2-MMP.
Specific Aim #3 : To determine whether local administration of RGD-conjugated splice shifting morpholino (cRGD.KDR.MO) can significantly increase sKDR/mKDR ratios and decrease neovascularization in laser-CNV injury and sutured corneas of wild type mice, and in Pax6+/- mouse corneas. These studies will define the tissue-specific functions of sFlt1 and sKDR in the context of competing requirements for neuronal and vascular homeostasis in the cornea, systematically detailing the development and maintenance of vascular zoning and neurite outgrowth in normal and pathological situations.
In blinding conditions such as aniridia and age-related macular degeneration, vascular control mechanisms in the eye are disrupted, leading to pathological invasion of blood vessels into the cornea or choroid as well as disruptions in neuronal homeostasis. This work will determine mechanisms of ocular angiogenic privilege as well as insights into the homeostasis of neurovascular patterning in physiologic and pathologic states.
| Cho, Yang K; Kwon, Jin W; Konda, Sneha et al. (2018) Epithelial Keratitis After Cataract Surgery. Cornea 37:755-759 |
| Mukhtar, Sabrina; Ambati, Balamurali K (2018) Pediatric keratoconus: a review of the literature. Int Ophthalmol 38:2257-2266 |
| Bowen, Randy C; Zhou, Andrew Xingyu; Bondalapati, Sailaja et al. (2018) Comparative analysis of the safety and efficacy of intracameral cefuroxime, moxifloxacin and vancomycin at the end of cataract surgery: a meta-analysis. Br J Ophthalmol 102:1268-1276 |
| Singh, Malkit K; Ambati, Balamurali K; Crandall, Alan S (2017) New capsular tension segment with 2-point fixation for zonular weakness. J Cataract Refract Surg 43:590-592 |
| Bondalapati, Sailaja; Ambati, Bala (2017) Intraocular foreign body removal: a novel technique using intraoperative imaging. Int Ophthalmol 37:749-752 |
| Ambati, Balamurali (2017) Re: Schwartz et al.: Intracameral antibiotics and cataract surgery: endophthalmitis rates, cost, and stewardship (Ophthalmology. 2016;123:1411-1413). Ophthalmology 124:e42-e43 |
| Lambert, Nathan G; ElShelmani, Hanan; Singh, Malkit K et al. (2016) Risk factors and biomarkers of age-related macular degeneration. Prog Retin Eye Res 54:64-102 |
| Yasuma, Reo; Cicatiello, Valeria; Mizutani, Takeshi et al. (2016) Intravenous immune globulin suppresses angiogenesis in mice and humans. Signal Transduct Target Ther 1: |
| Bogdanovich, Sasha; Kim, Younghee; Mizutani, Takeshi et al. (2016) Human IgG1 antibodies suppress angiogenesis in a target-independent manner. Signal Transduct Target Ther 1: |
| Gupta, Isha; Cahoon, Judd; Zhang, Xiaohui et al. (2015) In vivo ZW800-microbead imaging of retinal and choroidal vascular leakage in mice. Exp Eye Res 134:155-8 |
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