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Article ; Online: Next Generation Tissue Engineering: Inspired Models for Ophthalmic Drug Discovery.

Jayagopal, Ashwath / Ragelle, Héloïse

Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics

2019 Volume 36, Issue 1, Page(s) 3

MeSH term(s)	Animals ; Drug Discovery ; Humans ; Lab-On-A-Chip Devices ; Ophthalmic Solutions/chemical synthesis ; Ophthalmic Solutions/chemistry ; Tissue Engineering
Chemical Substances	Ophthalmic Solutions
Language	English
Publishing date	2019-10-01
Publishing country	United States
Document type	Introductory Journal Article
ZDB-ID	1237021-6
ISSN	1557-7732 ; 1080-7683
ISSN (online)	1557-7732
ISSN	1080-7683
DOI	10.1089/jop.2019.0101
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Article: Engineering of Nanoscale Contrast Agents for Optical Coherence Tomography.

Gordon, Andrew Y / Jayagopal, Ashwath

Journal of nanomedicine & nanotechnology

2014 Volume Suppl 5, Page(s) 4

Abstract: Optical coherence tomography has emerged as valuable imaging modalityin ophthalmology and other fields by enabling high-resolution three-dimensional imaging of tissue. In this paper, we review recent progress in the field of contrast-enhanced optical ... ...

Abstract	Optical coherence tomography has emerged as valuable imaging modalityin ophthalmology and other fields by enabling high-resolution three-dimensional imaging of tissue. In this paper, we review recent progress in the field of contrast-enhanced optical coherence tomography (OCT). We discuss exogenous and endogenous sources of OCT contrast, focusing on their use with standard OCT systems as well as emerging OCT-based imaging modalities. We include advances in the processing of OCT data that generate improved tissue contrast, including spectroscopic OCT (SOCT), as well as work utilizing secondary light sources and/or detection mechanisms to create and detect enhanced contrast, including photothermal OCT (PTOCT) and photoacoustic OCT (PAOCT). Finally, we conclude with a discussion of the translational potential of these developments as well as barriers to their clinical use.
Language	English
Publishing date	2014-06-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2712002-8
ISSN	2157-7439
ISSN	2157-7439
DOI	10.4172/2157-7439.S5-004
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Article ; Online: Organ-On-A-Chip Technologies for Advanced Blood-Retinal Barrier Models.

Ragelle, Héloïse / Goncalves, Andreia / Kustermann, Stefan / Antonetti, David A / Jayagopal, Ashwath

Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics

2019 Volume 36, Issue 1, Page(s) 30–41

Abstract: The blood-retinal barrier (BRB) protects the retina by maintaining an adequate microenvironment for neuronal function. Alterations of the junctional complex of the BRB and consequent BRB breakdown in disease contribute to a loss of neuronal signaling and ...

Abstract	The blood-retinal barrier (BRB) protects the retina by maintaining an adequate microenvironment for neuronal function. Alterations of the junctional complex of the BRB and consequent BRB breakdown in disease contribute to a loss of neuronal signaling and vision loss. As new therapeutics are being developed to prevent or restore barrier function, it is critical to implement physiologically relevant
MeSH term(s)	Animals ; Blood-Retinal Barrier/metabolism ; Humans ; Lab-On-A-Chip Devices ; Models, Biological ; Retina/metabolism
Language	English
Publishing date	2019-05-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1237021-6
ISSN	1557-7732 ; 1080-7683
ISSN (online)	1557-7732
ISSN	1080-7683
DOI	10.1089/jop.2019.0017
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Article ; Online: Imaging of cell populations in atherosclerosis using quantum dot nanocrystals.

Trantum, Joshua R / Jayagopal, Ashwath

Methods in molecular biology (Clifton, N.J.)

2013 Volume 1026, Page(s) 35–44

Abstract: Atherosclerosis, a leading cause of morbidity and mortality worldwide, is characterized by the accumulation of lipid deposits inside arterial walls, leading to narrowing of the arterial lumen. A significant challenge in the development of diagnostic and ... ...

Abstract	Atherosclerosis, a leading cause of morbidity and mortality worldwide, is characterized by the accumulation of lipid deposits inside arterial walls, leading to narrowing of the arterial lumen. A significant challenge in the development of diagnostic and therapeutic strategies is to elucidate the contribution of the various cellular participants, including macrophages, endothelial cells, and smooth muscle cells, in the initiation and progression of the atheroma. This protocol details a strategy using quantum dot nanocrystals to monitor homing and distribution of cell populations within atherosclerotic lesions with high signal to noise ratios over prolonged periods of analysis. This fluorescence-based approach enables the loading of quantum dots into cells such as macrophages without perturbing native cell functions in vivo, and has been used for the multiplexed imaging of quantum dot-labeled cells with biomarkers of atherosclerotic disease using conventional immunofluorescence techniques.
MeSH term(s)	Animals ; Apolipoproteins E/deficiency ; Atherosclerosis/pathology ; Biological Transport ; Cell-Penetrating Peptides/chemistry ; Immunomagnetic Separation ; Intracellular Space/metabolism ; Macrophages/metabolism ; Macrophages/pathology ; Mice ; Molecular Imaging/methods ; Quantum Dots ; Scorpion Venoms/chemistry
Chemical Substances	Apolipoproteins E ; Cell-Penetrating Peptides ; Scorpion Venoms ; maurocalcine
Language	English
Publishing date	2013
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-62703-468-5_3
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Article ; Online: ISOPT

Kompella, Uday B / Domb, Abraham / Urtti, Arto / Jayagopal, Ashwath / Wilson, Clive G / Tang-Liu, Diane

Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics

2019 Volume 35, Issue 8, Page(s) 457–465

Abstract: Ocular drug delivery offers unique challenges and opportunities in the era of novel therapeutic agents ranging from small molecules to gene therapies. Noninvasive delivery of drugs into the back of the eye or any part of the eye is extremely limited by ... ...

Abstract	Ocular drug delivery offers unique challenges and opportunities in the era of novel therapeutic agents ranging from small molecules to gene therapies. Noninvasive delivery of drugs into the back of the eye or any part of the eye is extremely limited by short precorneal residence time and formidable biological barriers. The eye is a sensitive, sensory organ that requires a high level of material and procedural safety, while achieving therapeutic efficacy. Some recent advances and unmet needs for ocular drug delivery and disposition are discussed in this article. Specifically, nanomedicines, physical and chemical means to enhance delivery, stimuli-responsive delivery systems, the role of vitreal binding on ocular pharmacokinetics, and the influence of aging eye on drug delivery, and the associated unmet needs are highlighted. Additionally, the unmet needs in the medication management for the elderly patients with eye diseases are discussed.
MeSH term(s)	Administration, Ophthalmic ; Aging/metabolism ; Animals ; Drug Carriers/chemistry ; Drug Delivery Systems/methods ; Eye Diseases/drug therapy ; Eye Diseases/metabolism ; Humans ; Nanotechnology ; Precision Medicine ; Tissue Distribution ; Vitreous Body/metabolism
Chemical Substances	Drug Carriers
Language	English
Publishing date	2019-06-28
Publishing country	United States
Document type	Congress ; Research Support, N.I.H., Extramural
ZDB-ID	1237021-6
ISSN	1557-7732 ; 1080-7683
ISSN (online)	1557-7732
ISSN	1080-7683
DOI	10.1089/jop.2018.0138
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Article ; Online: Indocyanine green molecular angiography of choroidal neovascularization.

Feenstra, Derrick J / Seleci, Muharrem / Denk, Nora / Fauser, Sascha / Drawnel, Faye M / Jayagopal, Ashwath

Experimental eye research

2018 Volume 180, Page(s) 122–128

Abstract: Retinal diseases such as proliferative diabetic retinopathy and neovascular AMD are characterized by the formation of new blood vessels. Current imaging techniques such as fluorescein and ICG angiography help to identify areas of vascular leakage but are ...

Abstract	Retinal diseases such as proliferative diabetic retinopathy and neovascular AMD are characterized by the formation of new blood vessels. Current imaging techniques such as fluorescein and ICG angiography help to identify areas of vascular leakage but are limited in their applicability due to their nonspecific nature. However, as new treatment paradigms emerge in an effort to have patient specific treatments, the development of new imaging techniques that are capable of identifying patient specific biomarkers will become crucial for the success of these approaches. In this study, we create and characterize an endoglin (CD105) targeted imaging probe that can be used for indocyanine green (ICG) molecular angiography. This anti-endoglin-ICG bioconjugate has a self-quenching "off-on" capacity to enable high contrast imaging of proliferative blood vessels at a molecular level in vivo. Using the laser CNV mouse model we demonstrate an approximate 3-fold increase in lesion visualization compared to non-targeting controls.
MeSH term(s)	Animals ; Cells, Cultured ; Choroidal Neovascularization/diagnosis ; Choroidal Neovascularization/metabolism ; Coloring Agents/administration & dosage ; Disease Models, Animal ; Electrophoresis, Polyacrylamide Gel ; Endoglin/metabolism ; Endothelium, Vascular/metabolism ; Fluorescein Angiography ; Indocyanine Green/administration & dosage ; Laser Coagulation ; Male ; Mice ; Mice, Inbred C57BL
Chemical Substances	Coloring Agents ; Endoglin ; Eng protein, mouse ; Indocyanine Green (IX6J1063HV)
Language	English
Publishing date	2018-12-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80122-7
ISSN	1096-0007 ; 0014-4835
ISSN (online)	1096-0007
ISSN	0014-4835
DOI	10.1016/j.exer.2018.12.016
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Article ; Online: In Vivo Imaging of Retinal Hypoxia Using HYPOX-4-Dependent Fluorescence in a Mouse Model of Laser-Induced Retinal Vein Occlusion (RVO).

Uddin, Md Imam / Jayagopal, Ashwath / McCollum, Gary W / Yang, Rong / Penn, John S

Investigative ophthalmology & visual science

2017 Volume 58, Issue 9, Page(s) 3818–3824

Abstract: Purpose: To demonstrate the utility of a novel in vivo molecular imaging probe, HYPOX-4, to detect and image retinal hypoxia in real time, in a mouse model of retinal vein occlusion (RVO).: Methods: Retinal vein occlusion was achieved in adult mice ... ...

Abstract	Purpose: To demonstrate the utility of a novel in vivo molecular imaging probe, HYPOX-4, to detect and image retinal hypoxia in real time, in a mouse model of retinal vein occlusion (RVO). Methods: Retinal vein occlusion was achieved in adult mice by photodynamic retinal vein thrombosis (PRVT). One or two major retinal vein(s) was/were occluded in close proximity to the optic nerve head (ONH). In vivo imaging of retinal hypoxia was performed using, HYPOX-4, an imaging probe developed by our laboratory. Pimonidazole-adduct immunostaining was performed and used as a standard ex vivo method for the detection of retinal hypoxia in this mouse RVO model. The retinal vasculature was imaged using fluorescein angiography (FA) and isolectin B4 staining. Retinal thickness was assessed by spectral-domain optical coherence tomography (SD-OCT) analysis. Results: By application of the standard ex vivo pimonidazole-adduct immunostaining technique, retinal hypoxia was observed within 2 hours post-PRVT. The observed hypoxic retinal areas depended on whether one or two retinal vein(s) was/were occluded. Similar areas of hypoxia were imaged in vivo using HYPOX-4. Using OCT, retinal edema was observed immediately post-PRVT induction, resolving 8 days later. Nominal preretinal neovascularization was observed at 10 to 14 days post-RVO. Conclusions: HYPOX-4 is an efficient probe capable of imaging retinal hypoxia in vivo, in RVO mice. Future studies will focus on its use in correlating retinal hypoxia to the onset and progression of ischemic vasculopathies.
MeSH term(s)	Animals ; Disease Models, Animal ; Fluorescein Angiography ; Fluoresceins/administration & dosage ; Fluoresceins/chemical synthesis ; Fluorescent Dyes/administration & dosage ; Fluorescent Dyes/chemical synthesis ; Hypoxia/diagnostic imaging ; Image Processing, Computer-Assisted ; Macular Edema/diagnosis ; Male ; Mice ; Mice, Inbred C57BL ; Nitroimidazoles/administration & dosage ; Nitroimidazoles/chemical synthesis ; Radiation-Sensitizing Agents/administration & dosage ; Retinal Neovascularization/diagnosis ; Retinal Vein/diagnostic imaging ; Retinal Vein Occlusion/diagnostic imaging ; Tomography, Optical Coherence
Chemical Substances	Fluoresceins ; Fluorescent Dyes ; HYPOX-4 compound ; Nitroimidazoles ; Radiation-Sensitizing Agents ; pimonidazole (46JO4D76R2)
Language	English
Publishing date	2017-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.16-21187
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Article ; Online: High Glucose-induced Retinal Pericyte Apoptosis Depends on Association of GAPDH and Siah1.

Suarez, Sandra / McCollum, Gary W / Jayagopal, Ashwath / Penn, John S

The Journal of biological chemistry

2015 Volume 290, Issue 47, Page(s) 28311–28320

Abstract: Diabetic retinopathy (DR) is a leading cause of blindness worldwide, and its prevalence is growing. Current therapies for DR address only the later stages of the disease, are invasive, and have limited effectiveness. Retinal pericyte death is an early ... ...

Abstract	Diabetic retinopathy (DR) is a leading cause of blindness worldwide, and its prevalence is growing. Current therapies for DR address only the later stages of the disease, are invasive, and have limited effectiveness. Retinal pericyte death is an early pathologic feature of DR. Although it has been observed in diabetic patients and in animal models of DR, the cause of pericyte death remains unknown. A novel pro-apoptotic pathway initiated by the interaction between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the E3 ubiquitin ligase, seven in absentia homolog 1 (Siah1), was recently identified in ocular tissues. In this article we examined the involvement of the GAPDH/Siah1 interaction in human retinal pericyte (hRP) apoptosis. HRP were cultured in 5 mm normal glucose, 25 mm l- or d-glucose for 48 h (osmotic control and high glucose treatments, respectively). Siah1 siRNA was used to down-regulate Siah1 expression. TAT-FLAG GAPDH and/or Siah1-directed peptides were used to block GAPDH and Siah1 interaction. Co-immunoprecipitation assays were conducted to analyze the effect of high glucose on the association of GAPDH and Siah1. Apoptosis was measured by Annexin V staining and caspase-3 enzymatic activity assay. High glucose increased Siah1 total protein levels, induced the association between GAPDH and Siah1, and led to GAPDH nuclear translocation. Our findings demonstrate that dissociation of the GAPDH/Siah1 pro-apoptotic complex can block high glucose-induced pericyte apoptosis, widely considered a hallmark feature of DR. Thus, the work presented in this article can provide a foundation to identify novel targets for early treatment of DR.
MeSH term(s)	Apoptosis/drug effects ; Cell Nucleus/enzymology ; Cells, Cultured ; Gene Knockdown Techniques ; Glucose/administration & dosage ; Glucose/pharmacology ; Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism ; Humans ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Pericytes/drug effects ; Protein Transport ; Retina/cytology ; Retina/drug effects ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Nuclear Proteins ; Glyceraldehyde-3-Phosphate Dehydrogenases (EC 1.2.1.-) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; seven in absentia proteins (EC 2.3.2.27) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2015-10-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.682385
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Article ; Online: Imaging of endothelial progenitor cell subpopulations in angiogenesis using quantum dot nanocrystals.

Barnett, Joshua M / Penn, John S / Jayagopal, Ashwath

Methods in molecular biology (Clifton, N.J.)

2013 Volume 1026, Page(s) 45–56

Abstract: Over the last decade, research has identified a class of bone marrow-derived circulating stem cells, termed endothelial progenitor cells (EPCs), that are capable of homing to vascular lesions in the eye and contributing to pathological ocular ... ...

Abstract	Over the last decade, research has identified a class of bone marrow-derived circulating stem cells, termed endothelial progenitor cells (EPCs), that are capable of homing to vascular lesions in the eye and contributing to pathological ocular neovascularization (NV). In preclinical and biological studies, EPCs are -frequently identified and tracked using a intracellularly loaded fluorescent tracer, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbo cyanine perchlorate-labeled acetylated LDL (DiI-acLDL). However, this method is limited by photobleaching and insufficient quantum efficiency for long-term imaging applications. We have developed a method for conjugation of high quantum efficiency, photostable, and multispectral quantum dot nanocrystals (QD) to acLDL for long-term tracking of EPCs with improved signal-to-noise ratios. Specifically, we conjugated QD to acLDL (QD-acLDL) and used this conjugated fluorophore to label a specific CD34(+) subpopulation of EPCs isolated from rat bone marrow. We then utilized this method to track CD34(+) EPCs in a rat model of laser-induced choroidal neovascularization (LCNV) to evaluate its potential for tracking EPCs in ocular angiogenesis, a critical pathologic feature of several blinding conditions.
MeSH term(s)	Acetylation ; Animals ; Bone Marrow Cells/cytology ; Choroidal Neovascularization/pathology ; Endothelial Cells/pathology ; Immunomagnetic Separation ; Intracellular Space/metabolism ; Lipoproteins, LDL/metabolism ; Molecular Imaging/methods ; Neovascularization, Pathologic/pathology ; Quantum Dots ; Rats ; Retina/pathology ; Stem Cells/pathology
Chemical Substances	Lipoproteins, LDL
Language	English
Publishing date	2013
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-62703-468-5_4
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Article ; Online: Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy.

Nature communications

2022 Volume 13, Issue 1, Page(s) 6045

Abstract: The retinal pigment epithelium (RPE) plays an important role in the development of diabetic retinopathy (DR), a leading cause of blindness worldwide. Here we set out to explore the role of Akt2 signaling-integral to both RPE homeostasis and glucose ... ...

Abstract	The retinal pigment epithelium (RPE) plays an important role in the development of diabetic retinopathy (DR), a leading cause of blindness worldwide. Here we set out to explore the role of Akt2 signaling-integral to both RPE homeostasis and glucose metabolism-to DR. Using human tissue and genetically manipulated mice (including RPE-specific conditional knockout (cKO) and knock-in (KI) mice), we investigate whether Akts in the RPE influences DR in models of diabetic eye disease. We found that Akt1 and Akt2 activities were reciprocally regulated in the RPE of DR donor tissue and diabetic mice. Akt2 cKO attenuated diabetes-induced retinal abnormalities through a compensatory upregulation of phospho-Akt1 leading to an inhibition of vascular injury, inflammatory cytokine release, and infiltration of immune cells mediated by the GSK3β/NF-κB signaling pathway; overexpression of Akt2 has no effect. We propose that targeting Akt1 activity in the RPE may be a novel therapy for treating DR.
MeSH term(s)	Animals ; Cytokines/metabolism ; Diabetes Mellitus, Experimental/complications ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/metabolism ; Diabetic Retinopathy/etiology ; Epithelial Cells/metabolism ; Glucose/metabolism ; Glycogen Synthase Kinase 3 beta/genetics ; Glycogen Synthase Kinase 3 beta/metabolism ; Humans ; Mice ; NF-kappa B/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Retinal Pigment Epithelium/metabolism ; Retinal Pigments/metabolism
Chemical Substances	Cytokines ; NF-kappa B ; Retinal Pigments ; AKT1 protein, human (EC 2.7.11.1) ; AKT2 protein, human (EC 2.7.11.1) ; Akt1 protein, mouse (EC 2.7.11.1) ; Akt2 protein, mouse (EC 2.7.11.1) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-10-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-33773-0
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