Vascular Biology of the Retina

The large majority of irreversible blindness in the US is caused by pathology of the blood vessels of the eye. Penn's long-standing interest is in the molecular basis of retinal vascular disease. The over-arching goal of his research is to characterize the processes involved in retinal vascular inflammation and angiogenesis, and to begin to develop preventive strategies based on understanding gained from in vitro and in vivo studies. The Penn lab has the capability to isolate and culture a variety of primary cells from retinal tissue of several species, including retinal vascular endothelial cells, choroidal endothelial cells, retinal Müller glia, retinal pericytes, retinal microglia and retinal pigment epithelial cells – all of which are involved in vascular diseases of the retina. In addition, the lab uses a battery of in vivo models of vascular diseases of the eye including rodent models of retinopathy of prematurity, neovascular age-related degeneration and diabetic retinopathy. Using these in vitro and in vivo tools, Penn's research program focuses on pro-inflammatory and pro-angiogenic molecular signaling in the retina. In his research, Penn places an emphasis on both drug target identification and on development of novel pharmaco-therapeutics and methods of drug delivery to the eye.

Penn has been continuously funded by the National Eye Institute of NIH for 33 years. He currently serves on the advisory boards of three prominent foundations supporting eye research, and he is President of the International Society for Eye Research.

Through an enterprise called VO-CRO (Vanderbilt Ophthalmic Contract Research Organization), Penn’s lab currently holds 18 contracts with pharmaceutical companies to develop novel drugs for eye diseases. More information about VO-CRO can be found here: VO-CRO website 

An overview of the Penn lab's research interests and current projects can be found here: Penn lab overview

NFAT and retinal vascular homeostasis: The Penn lab currently has multiple projects directed at understanding the role of the transcription factor, NFAT, in diabetic retinopathy pathogenesis. First, we are investigating NFAT’s regulation of extracellular matrix expression in the development of basement membrane thickening – a hallmark of diabetic retinopathy. Second, we are characterizing the role of NFAT in the response of photoreceptors to diabetes-relevant stimuli.  Finally, we are determining NFAT isoform specificity in early pathogenic events related to retinal cytokine induction under diabetic conditions.

Epoxygenated lipids and their products in retinal vascular inflammation:  Epoxide lipids generated by Cytochrome P450 epoxygenases are anti-inflammatory, but their levels are limited by the soluble epoxide hydrolase enzyme. We are testing the hypothesis that epoxide levels are decreased in the diabetic retina due to altered expression of the enzymes that regulate them, and therefore elevating their levels would be beneficial for the early treatment of diabetic retinopathy.  Similarly, the lipid epoxide-derived endocannabinoids that are selective for cannabinoid receptor 2 (CB2) binding are also potently anti-inflammatory.  We are characterizing their roles in diabetic retinopathy and the efficacy associated with elevating their endogenous levels.

Novel biomarker imaging and drug delivery methods:  The properties of the eye allow for unique opportunities to image biomarkers in vivo. We are designing novel RNA-based molecular beacons and contrast agents to better understand early disease processes, and as a first step in developing targeted strategies for delivery of novel therapeutic agents.

Faculty

John S. Penn, Ph.D.

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john.s.penn@vumc.org

 

Dolly A, Padovani-Claudio, M.D., Ph.D.

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Dolly Ann Padovani-Claudio, M.D., Ph.D, is a physician-scientist in the pediatric ophthalmology division where she cares for children with ocular conditions. Her research aims to better understand the role of select chemokines, such as IL-8, in mediating inflammation and new vessel growth in the retina. IL-8 is elevated in the vitreous of patients with diabetic retinopathy, so the goal of Dr. Padovani-Claudio's project is to determine whether inhibitors of the IL-8 receptor, CXCR1/2, will be effective in pre-clinical models of diabetic retinopathy with the goal of quickly translating these therapeutics to the clinic.

dolly.a.padovani-claudio@vumc.org

 

 Imam Uddin, Ph.D.

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Imam Uddin, Ph.D, is a research instructor developing nanotechnologies and novel optical imaging methods to detect molecular changes in real-time, as well as silencing specific gene targets with nanoparticles. He is synthesizing oligonucleotide-conjugated nano-gold colloids for imaging and silencing levels of specific mRNA targets in living cells and tissues. He is currently investigating this new technology in animal models of common eye diseases. In addition, Uddin has developed HYPOX-4, a novel fluorescence-imaging probe capable of detecting retinal hypoxia in living animals.  

md.i.uddin@vumc.org

 

Irina De la Huerta, M.D., Ph.D.

Irina de la Huerta

Dr. Irina De la Huerta, M.D., Ph.D, is an assistant professor and a physician scientist caring for adults and children with retinal diseases. Her research investigates the hypothesis that photoreceptors, the light-sensing cells in the retina, accelerate the development of retinal vascular diseases such as diabetic retinopathy. She is combining advances in cell culture techniques, genetic and metabolic animal models, and high-throughput biology, with the overall goal of developing novel therapeutic interventions that target the early stages of diabetic retinopathy.

irina.de.la.huerta@vumc.org

 

Postdoctoral Fellows

Carla Ramos, Ph.D.

Carla Ramos

Carla Ramos, Ph.D, is a postdoctoral fellow.  Her research interest is to understand how glial cells (astrocytes, Müller cells, microglia) under diabetes-relevant conditions affect the functional integrity of the blood-retinal barrier (BRB). Dr. Ramos uses the Electric Cell-substrate Impedance Sensing (ECIS) system to discriminate between transcellular and paracellular transport of materials through endothelial monolayers. Additionally, she is studying how glial cells respond to diabetic retinopathy-associated stimuli using RNA sequencing.

carla.ramos@vumc.org
 

Graduate Students

Meredith Giblin

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Meredith Giblin is a graduate student interested in understanding the role of basement membrane thickening early in diabetic retinopathy progression. Her project seeks to understand how retinal cells contribute to the development of BM thickening by utilizing qRT-PCR and proteomics techniques to understand how retinal cells alter expression and deposition of BM components in response to diabetes-relevant stimuli. Additionally, Meredith hopes to understand how changes in BM constituency induce pathogenic behaviors in these retinal cells.

meredith.j.giblin@vanderbilt.edu

 

Cayla Ontko

Cayla Ontko

Cayla Ontko is a second year graduate student interested in studying the effects of epoxygenated fatty acids and endocannabinoids on retinal vascular inflammation in DR. Recent evidence has shown a positive correlation between retinal inflammation and DR progression/vision loss. Cayla studies the inflammatory pathways of DR to gain insight into better therapeutic intervention and therefore vision preservation in adults with diabetes. Currently she is focusing her studies on epoxygenated fatty acids and endocannabinoids, both of which may have anti-inflammatory potential.

cayla.ontko@vanderbilt.edu

 

Amy Stark

Amy Stark

amy.k.stark@vanderbilt.edu

 

Staff

Emily Chen; RA I

Kaitlin Costello; VO-CRO Manager

Ashley Galloway, PhD; RA II

Sara Jamal; RA I

Marvara Jhala; RA I

Minjae Kim; RA I

Gary McCollum, PhD; Senior Scientist

Angie Mudrick; Sr. Administrative Assistant

Jorge Nunez; RA I

Hannah Pendergrass; VO-CRO RA I

Stephen Priest; RA I

Kendra Phillips; RA I

Taylor Smith, MAcc; VO-CRO Financial Analyst

Fei Yang; VO-CRO RA I

Rong Yang, MD; RA III

 

Undergraduate Students

Rachel Lee

Ashtyn Moser

Isabel Schnelle

 

Capozzi, M.E., Savage, S.R., McCollum, G.W., Hammer, S.S., Yang, R., Bretz, C.A. and Penn, J.S. (2020) Peroxisome proliferator-activated receptor-β/δ mediates retinal leukostasis via CCL8 and CXCL10. Exp Eye Res. 2020 Jan;190:107885. PMID:31758977.

Cao, J., Yang, R., Smith, T.E., Evans, S., McCollum, G.W., Pomerantz, S.C., Petley, T., Harris, I.R. and Penn, J.S. (2019) Human umbilical tissue-derived cells secrete soluble vascular endothelial growth factor receptor 1 and inhibit choroidal neovascularization. Mol Ther Methods Clin Dev. 2019 May 22(14):37-46. PMC6586593.

Gordon, A.Y., Lapierre-Landry, M., Skala, M.C. and Penn, J.S. (2019) Gold nanorods for molecularly targeted retinal imaging using photothermal optical coherence tomography. Translat Vis Sci Tech. May 2019, 8(3): 18. PMC6519216.

Uddin, M.I., Kilburn, T.C., Yang, R., McCollum, G.W., Wright, D.W. and Penn, J.S. (2018) Targeted imaging of VCAM-1 mRNA in a mouse model of laser-induced choroidal neovascularization using antisense hairpin DNA-functionalized gold nanoparticles. ACS Mol Pharm. 3;15(12):5514-5520. PMID:30350640.

Capozzi, M.E. and Penn, J.S. (2018) Palmitic acid induces Müller cell inflammation that is potentiated by co-treatment with glucose. Nature Sci Rep. 2018 Apr 3;8(1):5459. PMC5889388.

Uddin, M.I., Jayagopal, A., Wong, A., McCollum, G.W., Wright, D.W. and Penn, J.S. (2018) Real-time imaging of VCAM-1 mRNA in TNF-α activated retinal microvascular endothelial cells using antisense hairpin-DNA functionalized gold nanoparticles. Nanomed. 14(1):63-71. PMC5742066.

Lapierre-Landry, M., Gordon, A., Penn, J.S. and Skala, M. (2017) In vivo photothermal optical coherence tomography of endogenous and exogenous contrast agents in the eye. Nature Sci Rep. 7, 9228. PMC5569082.

Uddin, M.I., Jayagopal, A., McCollum, G.W., Yang, R. and Penn, J.S. (2017) In vivo imaging of retinal hypoxia using HYPOX-4-dependent fluorescence in a mouse model of laser-induced retinal vein occlusion (RVO). Invest Ophthalmol Vis Sci. 58:3818–3824. PMC5531786.

Capozzi, M.E. and Penn, J.S. (2016) Linoleic acid is a diabetes-relevant stimulator of retinal inflammation in human retinal Müller cells and microvascular endothelial cells. J. Diabetes & Metab. 2016 Dec; 7(12): 718. PMC5215739.

Capozzi, M.E., Hammer, S.S., McCollum, G.W., Penn, J.S. (2016) Epoxygenated fatty acids inhibit retinal vascular inflammation. Nature Sci. Rep. 6, 39211. PMC5155241.

Uddin, M.I., Evans, S.M., Craft, J.R., Capozzi, M.E., McCollum, G.W., Yang, R., Marnett, L.J., Uddin, M.J., Jayagopal, A. and Penn, J.S. (2016) In vivo imaging of retinal hypoxia in a model of oxygen-induced retinopathy. Nature Sci. Rep. 6:31011. PMC4974503.

Xu, L., Ruan, G., Dai, H., Liu, A.C., Penn, J.S. and McMahon, D.G. (2016) Mammalian retinal Müller cells have circadian clock function. Mol. Vis. Mar 24, 2016; 22:275-283. PMC4812508.

Suarez, S., McCollum, G.W., Jayagopal, A., Penn, J.S. (2015) High glucose-induced retinal pericyte apoptosis depends on association of GAPDH and Siah1. J. Biol. Chem. 2015 Nov 20;290(47):28311-20. 2015 Oct 5. PMC4653686.

Bretz, C.A., Savage, S.R., Capozzi, M.E., Suarez, S., Penn, J.S. (2015) NFAT isoforms play distinct roles in TNFα-induced retinal leukostasis. Nature Sci. Rep. 5, 14963. PMC4630625.

Savage, S.R., McCollum, G.W., Yang, R., Penn, J.S. (2015) RNA-seq identifies a role for the PPARβ/δ inverse agonist GSK0660 in the regulation of TNFα-induced cytokine signaling in retinal endothelial cells. Mol. Vis. 2015 May 20; 21:568-76. PMC4443583.

Savage, S.R., Bretz, C.A., Penn, J.S. (2015) RNA-seq reveals a role for NFAT-signaling in human retinal microvascular endothelial cells treated with TNFα. PLoS One. 2015 Jan 24;10(1): e0116941. PMC4305319.

  • R01 EY007533 - Molecular Mechanisms of Retinal Vascular Disease
  • R01 EY023397 - In vivo Molecular Imaging of the Retina
  • R01 EY023639 - The Calcineurin/NFAT Signaling Axis in Diabetic Retinopathy Pathogenesis
  • R01 EY029693 - In Vivo Molecular Imaging of Vascular Disease of the Retina
  • K08 EY029006 - Retinal Vascular Inflammation and Angiogenesis in Diabetic Retinopathy
  • Reeves Foundation
  • Research to Prevent Blindness
  • Jean Love Foundation
  • Phyllis G. and William B. Snyder Foundation
  • 18 current research contracts with drug companies