Project Details
Projekt
Manipulation of ciliary WNT signalling to improve RPE maturation in vivo and in vitro.
Applicant
Professorin Helen May-Simera, Ph.D.
Subject Area
Cell Biology
Developmental Biology
Developmental Biology
Term
from 2018 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 399364546
Over 733 million people worldwide are affected by vision impairment and the cost of treating such eye related disorders amounts to over €2.3 trillion annually. The vertebrate eye contains numerous ciliated cell types, the most well known are the light sensitive photoreceptors in the outer retina. However defects in many other ciliated ocular cell types likely contribute to a vast number of syndromic and non-syndromic ocular diseases. Of particular interest is the retinal pigment epithelium (RPE), a ciliated monolayer epithelium, which supports the retina and is essential for visual transduction. We have shown that the primary cilium is required for regulation of WNT signalling during maturation of the RPE and likely contributes to phenotype progression. There are currently no treatment options available for cilia-associated retinal degeneration nor is it clear to what extent defective cilia in other cell types might contribute to disease pathogenesis. Our long-term goal is to identify cell-based therapies to counteract neuroretinal degeneration in patients with cilia related ocular disorders. Our objective in this application is to manipulate ciliary WNT signalling to improve RPE maturation. We will test pharmacologically active compounds that counteract the effect of disrupted ciliary WNT signalling in the RPE and reduce the rate of retinal degeneration in vivo. Furthermore, we want to apply this knowledge to better improve differentiation of iPSC-derived RPE in vitro in monoculture and 3D-organoid cultures. We propose the following three specific aims:Aim 1: In vitro application of potential drugs to improve iPS- derived RPE. Aim 2: In vivo application of potential drugs to reduce ocular cilia defects in the RPE. Aim 3: Characterisation of eye organoid RPE in control and cilia mutant iPS derived brain organoids Our central hypothesis is that we can improve RPE maturation in vivo and in vitro, in control and diseased states, via pharmacological manipulation of ciliary mediated WNT signalling. Our hypothesis is based upon published and preliminary data, in which we and others have shown WNT signalling defects during RPE maturation in ciliopathy models, and that of pharmacological inhibition of WNT signalling has been shown to improve ciliary related WNT defects in other systems.
DFG Programme
Priority Programmes
