Stem cells for therapeutics and exploration of mechanisms in Huntingtons disease

Embryonic stem cell lines have two fundamental attributes: they may be expanded indefinitely at an undifferentiated state, allowing for production of massive numbers of genetically specified cells, and they can be triffered to differentiate into any cell type, allowing for analysis of a specific population characterised by stage and type of differentiation. STEMHD aims at making use of these two attributes to explore the mechanisms of Huntingtons disease, using available human ES cell line derived from an embryo identified as expressing he mutant HD gene during a preimplantation genetic diagnosis procedure. Using this cell line, the consortium will:
(1) establish protocols to enrich ES cell progeny in phenotypes of interest. HD effects primarily a mature cell population of medium-spiny GABAergic neurons in the striatum, these will be obtained using pharmacological induction and selection in in vitro culture.
(2) Design and implement infrastructures for mass cell production and long term cultures of ES cells either undifferentiated or following guided differentiation, in order to exploit fully the intrinsic capacities of the ES cell line in the production of massive numbers of specifically differentiated cells.
(3) identify, using differential transcriptomics for the full human genome, "biomarkers" associated to the mutant gene in the HD-expressing ES cell progeny that will be used as test signals for subsequent analyses. Association of these molecular markers to the disease will be validated and selected using experimental cell models and patients samples;
(4) Explore mechanisms of the disease in the mutant HD expressing ES cells progeny using functional genomics (RNAi and gene overexpression) to determine proteins involved in signalling pathways attached to the HD mutation; and hypothesis driven approaches to introduce potential new partners into already known systems;
(5) perform high content drug screening on HD gene carrying ES cell progeny.