Skip to main content

Restoring Mueller glia cell – photoreceptor interactions with Crumbs

Objective

Mutations in the Crumbs homologue 1 (CRB1) gene cause photoreceptor degeneration resulting in progressive retinitis pigmentosa (RP) or Leber congenital amaurosis (LCA), which both currently are untreatable blinding diseases. CRB1 is localized in Mueller glia cells at a subapical region (SAR) adjacent to adherens junctions between Mueller glia cells and photoreceptors. Loss of CRB1 function results in loss of adhesion between Mueller glia cells and photoreceptors. This ultimately results in the death of photoreceptors and other retinal neurons with loss of vision at birth (LCA) or before the age of 20 years (progressive RP). Using fruitfly and mouse genetics we will analyze the biochemical, cellular, developmental and physiological functions of CRB1, its family member CRB3, and CRB1-interacting-proteins PALS1, PATJ and MUPP1, in function of the SAR and its role in cell-cell interactions. We will analyze the effect of loss of interaction between Mueller glia cells and photoreceptors and subsequent retinal degeneration in retinas lacking both CRB1 and CRB3, or lacking the CRB1-interacting protein PALS1. To further understand the role of these proteins in neural-glial interactions in general, we will also assess what role these molecules play during development. To develop a cure restoring the impaired interaction between glial cells and photoreceptors, we will explore the efficacy of Mueller glia progenitor cell transplantation in mouse retinas. In collaboration with a small enterprise we will also deliver clinical grade adeno-associated viral (AAV) gene therapy vectors to transfer and express human CRB1 specifically in Mueller glia cells lacking CRB1 function. At the end of the project we will develop a demonstration project using these vectors in clinical phase I/II tests.

Field of science

  • /medical and health sciences/clinical medicine/transplantation
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/genetics and heredity
  • /social sciences/sociology/demography/fertility
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /medical and health sciences/medical biotechnology/genetic engineering/gene therapy
  • /medical and health sciences/clinical medicine/ophthalmology

Call for proposal

FP7-HEALTH-2007-A
See other projects for this call

Funding Scheme

CP-FP - Small or medium-scale focused research project

Coordinator

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Address
Kloveniersburgwal 29 Het Trippenhuis
1011 JV Amsterdam
Netherlands
Activity type
Other
EU contribution
€ 1 068 443,10
Administrative Contact
Rikesh Balgobind (Mr.)

Participants (6)

AMSTERDAM MOLECULAR THERAPEUTICS (AMT) NV

Participation ended

Netherlands
EU contribution
€ 60 156,90
Address
Meibergdreef 61
1105BA Amsterdam
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
André Verwei (Mr.)
EBERHARD KARLS UNIVERSITAET TUEBINGEN
Germany
EU contribution
€ 348 883
Address
Geschwister-scholl-platz
72074 Tuebingen
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Thomas H. Wheeler-Schilling (Dr.)
MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany
EU contribution
€ 548 231
Address
Hofgartenstrasse 8
80539 Munich
Activity type
Other
Administrative Contact
Birgit Knepper (Dr.)
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France
EU contribution
€ 599 794
Address
Rue Michel Ange 3
75794 Paris
Activity type
Research Organisations
Administrative Contact
Béatrice Saint-Cricq (Ms.)
THE UNIVERSITY OF SHEFFIELD
United Kingdom
EU contribution
€ 303 142
Address
Firth Court Western Bank
S10 2TN Sheffield
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Gill Wells (Ms.)
STICHTING KATHOLIEKE UNIVERSITEIT
Netherlands
EU contribution
€ 71 250
Address
Geert Grooteplein Noord 9
6525 EZ Nijmegen
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Wim Van Oijen (Mr.)