Objective
Regulated intramembrane proteolysis (RIP) is of emerging importance in a broad range of physiological processes by abrogating or initiating downstream signalling events.
beta-Secretase is by far the most diverse RIP mechanism if not only for the many substrates it targets. It consists of a catalytic component, presenilin that requires nicastrin, pen-2 and aph-1 for activity. The targets of beta-secretase are type I transmembrane proteins with the prerequisite however of ectodomain shedding.
Since most of these substrates somehow function as cell surface receptors, we hypothesize that regulation of their dual processing essentially occurs at the surface or en route to the endosomal system. In most cases, little is known about the co-distribution of different substrates or their spatial organization between the different microdomains including their individual routes of entry in the cell.
Moreover, as evidenced from the analysis of PS deficient cells, we postulate that a crosstalk exists between presenilin and/or presenilin-associated beta-secretase activity and sorting/internalization of substrates.
To address these questions, we aim for a comparative imaging analysis of three known substrates, i.e. the amyloid precursor protein (APP), Notch and the more recent p75 neurotrophin receptor, p75NTR. For these substrates, their incorporation or exclusion from lipid rafts as well as their routes of entry will be under focus.
To study events at the cell surface, we will establish a cell-free assay of isolated plasma membranes heets derived from wild-type, beta-secretase deficient fibroblasts or neuronal cell lines. Live and confocal imaging of single and double fluorescently tagged substrates will allow us to explore the routes and delivery to the endosomal system.
Finally, it is of increasing importance to establish the trafficking route of these substrates as well as the exact site of their proteolysis to understand their individual vital biological functions in health and disease.
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 physical sciences optics microscopy super resolution microscopy
- natural sciences biological sciences biochemistry biomolecules lipids
- natural sciences physical sciences optics microscopy confocal microscopy
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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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)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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.
FP6-2005-MOBILITY-5
See other projects for this call
Funding Scheme
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.
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
ZWIJNAARDE
Belgium
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.