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A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited
Donita L Garland1, Rosario Fernandez-Godino, Inderjeet Kaur
1Ocular Genomics Institute and.
Insights
The complement system plays a critical role in the formation of basal deposits, an early stage of macular degeneration. Inhibiting complement activity in a mouse model prevented these deposits, suggesting a therapeutic target for vision loss.
Area of Science:
- Ophthalmology
- Genetics
- Immunology
Background:
- Macular degenerations are leading causes of vision loss, with genetic factors and complement system involvement implicated in their pathogenesis.
- Drusen formation is a hallmark of macular degeneration, preceded by the development of basal deposits.
- The precise mechanisms linking the complement system to macular degeneration remain unclear.
Purpose of the Study:
- To investigate the role of the complement system in the earliest stages of macular degeneration, specifically basal deposit formation.
- To utilize a mouse model of Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) to study basal deposit development.
Main Methods:
- Studied gene-targeted Efemp1(R345W/R345W) mice, a model for DHRD/ML, which exhibit extensive basal deposits.
- Performed proteomic analyses on Bruch's membrane/choroid to characterize basal deposit composition and identify immune-related proteins.
- Generated Efemp1(R345W/R345W):C3(-/-) double-mutant mice to genetically ablate the complement response.
Main Results:
- Proteomic analysis revealed basal deposits consist of abnormal amounts of extracellular matrix (ECM) components and altered immune-related proteins, including complement factors.
- Genetic ablation of the complement response in double-mutant mice significantly inhibited basal deposit formation.
- These findings highlight the critical involvement of the complement system in the pathogenesis of basal deposits.
Conclusions:
- The complement system plays a crucial role in the formation of basal deposits, an early event in certain macular degenerations.
- Complement-mediated recognition of abnormal extracellular matrix may drive basal deposit formation in DHRD/ML and potentially other macular degenerations.
- Targeting the complement system could offer a therapeutic strategy for preventing vision loss associated with macular degeneration.
Abstract:
Macular degenerations, inherited and age related, are important causes of vision loss. Human genetic studies have suggested perturbation of the complement system is important in the pathogenesis of age-related macular degeneration. The mechanisms underlying the involvement of the complement system are not understood, although complement and inflammation have been implicated in drusen formation. Drusen are an early clinical hallmark of inherited and age-related forms of macular degeneration. We studied one of the earliest stages of macular degeneration which precedes and leads to the formation of drusen, i.e. the formation of basal deposits. The studies were done using a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by a p.Arg345Trp mutation in EFEMP1. The hallmark of DHRD/ML is the formation of drusen at an early age, and gene targeted Efemp1(R345W/R345W) mice develop extensive basal deposits. Proteomic analyses of Bruch's membrane/choroid and Bruch's membrane in the Efemp1(R345W/R345W) mice indicate that the basal deposits comprise normal extracellular matrix (ECM) components present in abnormal amounts. The proteomic analyses also identified significant changes in proteins with immune-related function, including complement components, in the diseased tissue samples. Genetic ablation of the complement response via generation of Efemp1(R345W/R345W):C3(-/-) double-mutant mice inhibited the formation of basal deposits. The results demonstrate a critical role for the complement system in basal deposit formation, and suggest that complement-mediated recognition of abnormal ECM may participate in basal deposit formation in DHRD/ML and perhaps other macular degenerations.
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