Objective
We propose to investigate mechanisms by which bone morphogenetic protein 2 mediates osteogenesis in human bone marrow stromal cell cultures. Bone morphogenetic proteins (BMPs) are currently considered promising bone therapeutic agents because of their bone forming capacity in several animal models. Recombinant forms of BMP2 and 7 have been approved for the promotion of spinal fusions, treatment of open fractures and fracture non-unions. Other musculoskeletal applications of BMPs in humans have been less successful; some reports indicate large variations in response among individual patients and the need for much higher BMP doses to induce adequate bone formation in humans compared with animals.
One part of the problem may be poor osteogenic response of adult human bone marrow stromal cells (hMSC) to BMPs. Bone marrow stroma is a reservoir of osteoblast precursors, which can be induced to differentiate into osteoblasts upon demand. Our hypothesis is that BMP-mediated osteogenesis of hMSC from mature donors is negatively regulated by serum-induced high ERK activity and positively regulated by insulin or IGF-1 induced PI3-K signalling, while BMP-2 mediated osteogenic progression of hMSC from paediatric donors is less dependent on these co-regulatory pathways. Aim 1 tests the hypothesis that serum-activated ERK phosphorylates BMP-activated Smads, thus preventing Smad nuclear localization and transcriptional activity. Aim 2 investigates mechanisms by which the insulin/IGF-1 pathway interacts with the BMP signalling pathways to promote osteogenesis. Aim 3 tests the hypothesis that hMSC from young donors are less susceptible to ERK and PI3-K co-regulatory signalling, thus they are capable of BMP-mediated osteogenesis in a broader range of environments. We expect the results of this study to provide possible explanations for the frustrating results of some clinical trials and suggest potential approaches for improving the therapeutic efficacy of BMPs.
Fields of science (EuroSciVoc)
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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.
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Keywords
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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)
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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
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP6-2004-MOBILITY-12
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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.
IRG - Marie Curie actions-International re-integration grants
Coordinator
KRAKOW
Poland
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