Objective
The orphan nuclear receptor, liver receptor homology-1 (LRH-1), is highly expressed in liver and exocrine pancreas. Although LRH-1 has been shown to be involved in developmental and homeostatic processes, its integrated function remains at present ill-defined. This is in part due to the lack of adequate in vivo mouse models to characterize LRH-1. We propose to elucidate the role of LRH-1 specifically in the liver, by integrating state-of-the-art approaches in mouse genetics, physiology and functional genomic s. The strong genetic, developmental, physiological, and biochemical similarities between mouse and man justifies this approach. As homozygous LRH-1 deficient mice are embryonic lethal, we propose to "flox" the LRH-1 allele, enabling the generation of temp orally and spatially controlled, hepatocyte-specific, LRH-1 mutant mice.
This approach is particularly relevant in metabolic diseases where the pathology affects multiple organs. Using transcriptional profiling, we will obtain a comprehensive molecular fin gerprint to be correlated with the detailed clinical phenotype, in order to identify the signalling pathways controlled by LRH-1.
To complement this mouse model the regulation of LRH-1 activity will also be investigated. LRH-1 is constitutively active and ligands are indispensable for it's basal activity. Consequently, LRH-1 activity may be regulated through phosphorylation. The primary sequence of LRH-1 contains several potential consensus PKA, PKC and MARK phosphorylation sites, and their impact on LRH-1 a ctivity has not been fully elucidated.
Through the use of specific kinase inhibitors, site-directed mutagenesis, EMSA and cofactor recruitment assays the regulation of LRH-1 activity by kinases will be established. Thus this proposal will generate a mouse model, which will reveal the function of hepatic LRH-1 to physiology and pathophysiology, findings that will validate LRH-1 as a therapeutic target to combat disorders linked to its dysfunction in the liver.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics
- medical and health sciences basic medicine physiology pathophysiology
- medical and health sciences basic medicine pathology
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP6-2002-MOBILITY-5
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
IIIKIRCH
France
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.