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Models of Pathologies Associated with Age-Related Macular Degeneration and Their Utilities in Drug Discovery

  • Goldis MalekEmail author
  • Pei-Li Yao
  • Mayur Choudhary
Chapter
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Part of the Topics in Medicinal Chemistry book series

Abstract

Age-related macular degeneration is the leading cause of vision loss in the elderly in the developed world, with an ever-increasing prevalence in the developing world. The complexity of the disease and lack of effective therapies speak to the necessity of further understanding the pathobiology and mechanisms underlying initiation and progression of this retinal neurodegenerative disease, as well as identifying new therapeutic targets. Designing and characterizing cell culture and animal models that promulgate the human AMD condition provide preclinical avenues to address these two unmet needs. Herein we discuss strengths and weaknesses associated with current in vitro and in vivo models available that facilitate testing of potential AMD-targeting drugs and discovery of new pathways involved in disease development.

Keywords

Age-related macular degeneration (AMD) Animal models Choroidal endothelial cells (ChEC) Choroidal neovascularization (CNV) Lipid metabolism Oxidative stress Retinal organoids Retinal pigment epithelium (RPE) Sub-RPE deposits 

Abbreviations

A2E

Diretinoid-pyridinium-ethanolamine

ABCA1

ATP-binding cassette transporter A1

AhR

Aryl hydrocarbon receptor

AMD

Age-related macular degeneration

APOE

Apolipoprotein E

BrM

Bruch’s membrane

CDH5

Cadherin 5

CEP

Carboxyethylpyrrole

CETP

Cholesterol ester transfer protein

CFH

Complement factor H

ChEC

Choroidal endothelial cells

CNV

Choroidal neovascularization

CRALBP

Cellular retinaldehyde-binding protein

CSE

Cigarette smoke extract

CX3CR1

C-X3-C motif chemokine receptor 1

DHA

Docosahexaenoic acid

ECM

Extracellular matrix

EGFR

Epidermal growth factor receptor

EMT

Epithelial-mesenchymal transition

ERK

Extracellular signal-regulated kinases

ESC-RPE

Embryonic stem cell-derived RPE cells

FAK

Focal adhesion kinase

FBS

Fetal bovine serum

GWAS

Genome-wide association study

H2O2

Hydrogen peroxide

HDL

High-density lipoprotein

HFD

High-fat diet

hfRPE

Human fetal RPE cells

HMGCS2

3-Hydroxy-3-methylglutaryl-coA synthase 2

HPV

Human papilloma virus

INSIG1

Insulin-induced gene-1

iPSC-RPE

Induced pluripotent stem cell-derived RPE

KEAP1

Kelch-like ECH-associated protein 1

LDL

Low-density lipoproteins

LIPC

Hepatic lipase

NRF2

Nuclear factor 2

OCT

Optical coherence tomography

OCT3/4

Octamer-binding transcription factor ¾

PAX6

Paired box 6

PECAM1

Platelet and endothelial cell adhesion molecule 1

PLVAP

Plasmalemma vesicle-associated protein

PPARβ/δ

Proliferator-activated receptor beta/delta

RAL

Retinaldehyde

RDH

All-trans-retinol dehydrogenases

ROS

Reactive oxygen species

RPE

Retinal pigment epithelium

RPESC

Retinal pigment epithelial stem cells

SOD

Superoxide dismutase

SRC

Src proto-oncogene, non-receptor tyrosine kinase

SYK

Spleen associated tyrosine kinase

TGFBR1

TGFβ type I receptor

TGFβ

Transforming growth factor beta

TSPO

Translocator protein

VEGFA

Vascular endothelial growth factor A

Vldlr

Very low-density lipoprotein receptor

ZO1

Zonula occludens 1

Notes

Acknowledgments

We thank our funding agencies [National Eye Institute grants R01 EY027802 and R01 EY028160 (to GM), P30 EY005722 (to the Duke Eye Center), and the Research to Prevent Blindness, Inc. (RPB) Core grant (to the Duke Eye Center)] for their continued support of our ongoing research and quest to understand complex retinal diseases and identify new therapeutic targets. We also express our gratitude to the donors and their families for their generosity.

Compliance with Ethical Standards

Funding: This study was funded by National Eye Institutes grants R01 EY028702 and R01 EY028160 (to GM), P30 EY005722 (to the Duke Eye Center), and the Research to Prevent Blindness, Inc. (RPB) Core grant (to the Duke Eye Center).

Ethical Approval: Donor tissues obtained are used following approval from the Duke Institutional Review Board (IRB) committee. Similarly, animal studies are performed following protocol approval from the Duke Institutional Animal Care and Use Committee (IACUC).

Informed Consent: Not applicable.

Conflict of Interest: The authors have no conflicts of interest to disclose.

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Departments of Ophthalmology and Pathology, Albert Eye Research InstituteDuke UniversityDurhamUSA
  2. 2.Department of OphthalmologyDuke UniversityDurhamUSA

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