Establishment of a Mouse Model for Understanding How Plasma Proteins Called Complement May Cause the Dry Form of Age-related Macular Degeneration

Wenchao Song, PhD
University of Pennsylvania (Philadelphia , PA, United States)
Year Awarded:
2011
Grant Duration:
July 1, 2011 to June 30, 2013
Disease:
Macular Degeneration
Award Amount:
$100,000
Grant Reference ID:
M2011051
Award Type:
Standard
Award Region:
US Northeastern

Co-principal Investigators

Imran Mohammed, PhD
University of Pennsylvania

Complement Activation in RPE Function and AMD Pathogenesis

Summary

To create a mouse model and use it to understand the pathogenesis of age-related macular degeneration caused by complement, a group of plasma proteins involved in inflammation.

Details

There is no effective treatment available for the early or dry type of age‐related macular degeneration (AMD). One idea for future treatments sprung from the discovery that a group of blood proteins that helps the body to attack “foreign invaders,” called the complement system, may initiate dry AMD. Drs. Wenchao Song, Imran Mohammed, and collaborators will create mice that have had the genetic “brake” removed from the complement system. They suspect that this will cause severe inflammation and damage the retina in a way that will resemble dry AMD. If this is the case, then these mice could then be used as a model for testing new preventions and treatments for dry AMD.

Research Updates

Complement is part of the body’s defense system against viral and bacterial infections. Usually, it is controlled precisely so that it does not cause “friendly fire” and injure the body itself. However, if the control mechanism is not working properly, then complement can cause damage and disease. It is now known that improper complement activity contributes to the development of macular degeneration. In this project, Dr. Song’s and Dr. Mohammed’s team is trying to produce a mouse model whereby they disable the complement control mechanism specifically in the eye, in the hope that this will lead to retinal injury that more closely mimics human macular degeneration. The complement control mechanisms are multiple and often redundant, therefore they may need to disable more than one mechanism to be sufficient to cause severe eye disease.

During the past year, the team has achieved disabling one particular control mechanism in a special type of mouse. Preliminary examination showed that the mice exhibited some signs of retinal degeneration, which is really quite exciting to see after disabling only one type of complement control. While they are continuing to observe and study these mice to see if the retinal disease will get worse and resemble the type of macular degeneration seen in humans, they are also disabling a second control mechanism. The team hopes that by concurrently removing these two control mechanisms, complement activity in the retinal cells will be switched into overdrive that will cause severe and fast-developing retinal disease. Such a mouse model of disease will allow testing of new anti-complement drugs, which could eventually be developed and used in human patients with AMD.