Objective
Hypercholesterolemia, high levels of plasma LDL-cholesterol, is a major risk factor for atherosclerosis and premature coronary heart disease (CHD), the leading cause of death in developed countries. The clearance of LDL from the circulation occurs via endocytosis with the LDL-receptor (LDLR) mainly by liver cells. This hepatic recruitment of the LDL-LDLR complex to the clathrin-coated pits is dependent on the endocytic adaptor protein, autosomal recessive hypercholesterolemia (ARH). Consequently, naturally occurring mutations in either LDLR or in ARH lead to sever hypercholesterolemia and premature onset of CHD. Therefore, studying the molecular interactions ARH forms at the cell surface is central to our understanding of LDL internalization and cholesterol homeostasis.
Despite large body of structural data on the ecto-domain of LDLR, the structures of either ARH or the LDLR tail are unknown. To gain a detailed mechanistic understanding for the unique function of ARH, this proposal will investigate (1) The molecular basis for receptor recognition by solving crystal structures of ARH with receptor tails; (2) The interaction of ARH with phosphoinositides and with cell membrane via tools from cell biology and biochemistry; (3) The interaction of ARH with clathrin and its major endocytic adaptor AP-2 structurally and biochemically.
The multidisciplinary approach proposed here will significantly extends the molecular knowledge on sorting of LDLR to clathrin-coated pits which is highly significant for cellular physiology and for catabolism of plasma cholesterol and cardiovascular health.
Fields of science (EuroSciVoc)
- engineering and technology materials engineering crystals
- medical and health sciences clinical medicine cardiology cardiovascular diseases arteriosclerosis
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences cell biology
- medical and health sciences basic medicine physiology homeostasis
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.
FP7-PEOPLE-2012-CIG
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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.
MC-CIG - Support for training and career development of researcher (CIG)
Coordinator
32000 Haifa
Israel
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.