Analysis of ocular disease in familial adenomatous polyposis using pluripotent stem cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05839
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
Autosomal dominant mutations in the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP), resulting in colonic polyps that can progress to adenocarcinoma. FAP patients also have congenital hypertrophy/hyperplasia (abnormal growth)of the retinal pigmented epithelium (RPE), which can result in visual defects and ocular tumors. FAP can also result in retinal coloboma, a childhood neurological disease characterized by malformation of the retina. Investigation of APC function in animal models suggests that aberrant cellular signaling might account for abnormal ocular development by controlling retinoic acid production by RPE. Little is known, however, about APC function in human retina. We propose a collaborative project that utilizes human pluripotent stem cells harboring APC mutations. We hypothesize that APC plays a critical role in human RPE cells by 1) regulating control of proliferation, and 2) regulating retinoic acid signalling. S The availability of APC mutant human RPE cells will for the first time allow dissection of key molecular mechanisms and impact on our understanding of FAP - and RPE cell function. This will impact our understanding of a key cell type currently being used to treat age-related macular degeneration.
Statement of Benefit to California: 
Cancer and blindness represent a sizable burden to California's healthcare system. Autosomal dominant mutations in the adenomatous polyposis coli (APC) gene cause familial adenomatous polyposis (FAP), resulting in colonic polyps that can progress to adenocarcinoma. FAP patients also have congenital hypertrophy/hyperplasia of the retinal pigmented epithelium (RPE), which can result in visual defects and ocular tumors. FAP can also result in retinal coloboma, a childhood neurological disease characterized by malformation of the retina. Investigation of APC function in animal models suggests that aberrant signaling might account for abnormal ocular development by controlling retinoic acid production by RPE. Little is known, however, about APC function in human retina. This project will have impact and benefit to the state in that it will help people with disease and inform use of RPE cells in stem cell therapies for age related macular degeneration.

© 2013 California Institute for Regenerative Medicine