LDLRDS · Low density Lipoprotein receptors in development and signalling
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-12-01 → 2007-11-30
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- EIF
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Results in brief
Final Activity Report Summary - LDLRDS (Low density lipoprotein receptors in development and signaling)
Proteins of the low density lipoprotein receptor family (LDLRs) have essential biological roles. For example, one of the members of the family, the human LDLR, regulates cholesterol levels in plasma and its mutations lead to familial hypercholesterolemia. Other LDLRs play key roles during the development of organisms and their malfunction is linked to the Donnai-Barrow, facio-oculo-acoustico-renal and osteoporosis pseudoglioma syndromes. All LDLRs are structurally related proteins and more importantly, they are evolutionarily conserved. Thus, we find the same or very similar set of LDLRs in organisms as distant as the fly Drosophila, the nematode, zebrafish or humans. This structural and functional conservation allows us to use simple organisms with powerful genetics like Drosophila to study the functions of LDLRs. In this project, we have done the initial characterisation of four LDLRs in the fly. Two of these genes, that we called lipophorin receptor 1 and 2, are related to the human LDLR and similarly to it, regulate lipid metabolism. Flies that are mutant for the lipophorin receptors are unable to efficiently mobilise their lipid reserves during starvation. At the cellular level, lipophorin receptors mediate the uptake of lipids from the surrounding hemolyph. Our results validate and increase the usefulness of Drosophila as a model organism to study pathologies related to energy balance regulation, like obesity, diabetes and metabolic syndrome. We have also identified and done the initial genetic and molecular characterisation of the fly lrp1 gene. Our results show that this gene modulates the activity of the TGF-beta signalling pathway, a key regulator of multiple biological processes that is involved in cancer pathogenesis, neurodegeneration and atherosclerosis. These studies are the foundation for a better understanding of the interplay between LRP1 and TGF- beta.
Data: CORDIS, © European Union
Project objective
The low-density lipoprotein receptor family (LDLRs) is an evolutionarily conserved group of structurally and functionally related proteins. Traditionally, they were involved in receptor-mediated endocytosis of a variety of cargo molecules, including lipoproteins. However, the discovery of additional members of the family revealed that several LDLRs also have signal-transduction activity and play critical roles during development. Our understanding of these signalling functions is still poor. Because of their multiple roles, LDLRs are involved in several human diseases and conditions like familial hypercholesterolemia, atherosclerosis, abnormal bone density or Alzheimer's disease.We propose the use of Drosophila melanogaster as an excellent model organism to study the signalling properties of LDLRs. First, we plan to obtain mutants for each of the five novel Drosophila LDLR genes, study their functions during development and to identify their potential roles in signal transduction. Second, we will design genetic screens to uncover the intracellular components necessary to transduce the signals received by LDLRs from the cell surface to the nucleus. We anticipate that a significant number of the cytoplasmic transducers we find in Drosophila will also be conserved and perform similar functions in mammals.Finally, a distinct part of this proposal relates to the biogenesis of LDLR proteins in cells. We recently identified a molecular chaperone that is specifically required for the maturation of LDLRs in the endoplas micreticulum and that we named Boca. We will extend our results to better define the biochemical activity of Boca.
Original text from CORDIS.
Participants
- CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS · MADRIDCoordinatorSpain
Links
Data: CORDIS, © European Union