Funding opportunities

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

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05839
Funds requested: 
$1 333 800
Funding Recommendations: 
Not recommended
Grant approved: 
No
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.
Review Summary: 
Familial adenomatous polyposis (FAP) caused by mutations in the adenomatous polyposis coli (APC) gene is sometimes accompanied by abnormal growth of retinal pigmented epithelium (RPE) cells. This condition can lead to visual defects, although the molecular mechanisms underlying this phenotype are largely unknown. This application proposes to study the effect of mutant APC in hESC- and iPSC-derived RPE cell lines and to test the role of APC in in the regulation of retinoic acid and Wnt signaling in RPE. The availability of APC mutant human RPE cells will allow dissection of key molecular mechanisms underlying RPE cell function and contribute to a greater understanding of FAP. Significance and Innovation - The effect of APC mutations on visual function appears to be small, so it is unclear that the proposed study will have significant impact on the understanding and treatment of vision diseases. - Although the study of APC mutations in RPE represents an innovative approach, APC mutations have been shown to affect the Wnt pathway in other cell types, and the dual roles for APC in regulating retinoic acid biosynthesis and Wnt during ocular development has been previously reported. - Since only ~40% of the patients with APC mutations develop RPE changes, the proposed studies may have significance if the investigators carefully correlate the mutations with clinical changes to the RPE. Feasibility and Experimental Design - Since many family members with APC mutations do not exhibit RPE changes, there may be some, as yet unidentified, component necessary for development of the ocular changes associated with the systemic nature of the disease. - The preliminary data provided are modest but do demonstrate some success in generating APC expressing RPE cells from both hESC and iPSC from normal tissue. - Reviewers questioned the value and suitability of assays proposed for evaluation of mutant APC effects on RPE cells, as preliminary data did not adequately validate the utility of these assays. - Reviewers indicated that aim 3 was poorly described and lacking in essential details. Principle Investigator and Research Team - The PI is productive, well funded and an expert in RPE biology. - Reviewers were mixed on the value of the proposed collaboration; some considered it a strong asset while others were less certain. Responsiveness - The proposal meets the objectives of the RFA and was viewed as entirely responsive.
Conflicts: 

© 2013 California Institute for Regenerative Medicine