Complement is an important form of innate immunity that plays a key role in host defense. However, recent studies have revealed that it is also implicated in many human diseases, both rare and common. One of the high-prevalence diseases that have been linked to abnormal complement activation is age-related macular degeneration (AMD), a progressive blinding condition in the elderly. Genetic studies have provided evidence that individuals carrying single nucleotide polymorphism (SNP) in complement genes such as complement factor H (fH), factor B (fB), component 2 (C2) and component 3 (C3) are at increased risk of developing AMD. Although mouse models have been developed to study the role of complement in wet AMD with choroidal neovascularization (CNV) as an endpoint, and several anti-complement agents are being evaluated in clinical trials for wet AMD, better understanding of the role of complement in the development of dry AMD is required, and will be aided by development of animal models. RPE dysfunction is an overlapping pathological cause for both dry and wet AMD. In this project, we will study the pathogenesis of RPE dysfunction and retinal injury in the context of abnormal complement activation in the eye. We have created a mouse model by selectively deleting a key membrane complement regulator Crry in RPE cells. Crry is a murine C3 convertase inhibitor that is considered a functional homolog of human membrane cofactor protein (MCP, CD46). CD46 is down- regulated in the RPE in regions of expanding geographic atrophy (GA), making it a disease-relevant target. By using the cre-lox conditional gene targeting strategy, we selectively inactivated the Crry gene in RPE cells, modeling loss of CD46 in GA. Preliminary characterization of the RPE-specific Crry knockout (KO) mice revealed local complement activation together with features of RPE degeneration akin to human dry AMD. Furthermore, the mutant mice developed sub-RPE deposits and neurosensory retinal dysfunction. The RPE- specific Crry KO mouse thus represents a novel animal model that develops complement-mediated RPE degeneration/deposits with features of dry AMD. The overall objective of this proposal is to use the RPE- specific Crry KO mouse and investigate the mechanism of action of dysregulated complement in the pathogenesis of retinal degeneration, to define the complement mediators responsible and to explore anti- complement therapies for this disorder. These studies will help guide future anti-complement clinical trials with respect to effective complement cascade targets and routes of administration.

Public Health Relevance

This project uses a transgenic mouse model to study an eye disease that resembles a human blinding disorder called age-related macular degeneration (AMD) that is common in elderly individuals. We will perform experiments to understand how the disease develops and test some new candidate drugs to prevent or reverse this disease in the animal model.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
4R01EY023709-04
Application #
9090120
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
Project Start
2013-08-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gullipalli, Damodar; Zhang, Fengkui; Sato, Sayaka et al. (2018) Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis. J Immunol 201:1021-1029
Ueda, Yoshiyasu; Mohammed, Imran; Song, Delu et al. (2017) Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation. Blood 129:1184-1196
Song, Delu; Sulewski Jr, Michael E; Wang, Chenguang et al. (2017) Complement C5a receptor knockout has diminished light-induced microglia/macrophage retinal migration. Mol Vis 23:210-218
Li, Yafeng; Song, Delu; Song, Ying et al. (2015) Iron-induced Local Complement Component 3 (C3) Up-regulation via Non-canonical Transforming Growth Factor (TGF)-? Signaling in the Retinal Pigment Epithelium. J Biol Chem 290:11918-34