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.
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