Award details

Modelling the Gene Regulatory Network underlying Lineage Commitment in Human Mesenchymal Stem Cells (LINCONET)

Reference	BB/I004556/1
Principal Investigator / Supervisor	Professor Francesco Falciani
Co-Investigators / Co-Supervisors
Institution	University of Birmingham
Department	Sch of Biosciences
Funding type	Research
Value (£)	270,583
Status	Completed
Type	Research Grant
Start date	01/03/2010
End date	30/04/2013
Duration	38 months

Abstract

With the aging of the world population, degenerative diseases such as osteoporosis and arthritis will have an increasing impact on health and quality of life. Restoration of damaged bone and cartilage by stimulating human mesenchymal stem cells (HMSCs) to differentiate into bone- or cartilage-synthesizing cells provides a novel and attractive therapeutic opportunity with profound implications in biomedicine. This requires a thorough understanding of normal lineage commitment of HMSCs as well as an understanding of the key pathogenetic players in disease-induced tissue degradation. Given the multi-potent character of stem cells, and the complexity of the cross-talk between signalling pathways that determine lineage commitment and disease progression, a systems biological approach is essential to understand this process. This project aims to develop a systems biology framework to understand tissue regeneration and to identify key genes affected by tissue degeneration processes in different forms of arthritis. To this end, we will unravel and mechanistically model the genetic network underlying normal lineage commitment of HMSCs and, in parallel, discover genes that are aberrantly expressed in the diseased bone- or cartilage-synthesizing cells. The integration of both approaches is pivotal for raising hypotheses towards disease-modifying gene products important for the restoration of bone or cartilage. An integral part of our strategy is to experimentally validate hypotheses generated by computational models by using tightly integrated cycles of computational modelling and experimental verification at the cellular and organism level.

Summary

With the aging of the world population, degenerative diseases such as osteoporosis and arthritis will have an increasing impact on health and quality of life. Restoration of damaged bone and cartilage by stimulating human mesenchymal stem cells (HMSCs) to differentiate into bone- or cartilage-synthesizing cells provides a novel and attractive therapeutic opportunity with profound implications in biomedicine. This requires a thorough understanding of the normal biological processes underlying cell differentiation and the disease-induced tissue degeneration. Given the multi-potent character of stem cells, and the complexity of the cross-talk between signalling pathways that determine lineage commitment and disease progression, an integrated approach that uses advanced computational techniques (a systems biology approach) is essential. This project aims to develop a framework to understand tissue regeneration. To this end, we will unravel and mechanistically model the genetic network underlying normal tissue regeneration processes. An integral part of our strategy is to experimentally validate hypotheses generated by computational models by using tightly integrated cycles of computational modelling and experimental verification at the cellular and organism level.

Impact Summary

This project will result in increased knowledge about the molecular mechanisms and key regulators that control normal lineage-specific commitment and differentiation of HMSC. In addition, this project will give insight into the key genes affected by OA and RA. Functional validations performed in this project concerning the role of druggable key genes will have a major contribution to the development of novel therapies for the treatment of degenerative disorders such as osteoporosis and arthritis. We expect therefore that our research will benefit the public and private sector at several levels. The development of data analysis methodologies for the inference of regulatory networks from observational data is in fact a very new area where organizations interested in the development of bio-markers of clinical relevance are investing a considerable amount of resources. Our methodologies will certainly represent a significant contribution to the field and will indeed directly benefit these organizations. More generally the identification of molecular networks controlling tissue differentiation and regeneration will represent potential important targets for the pharmaceutical industry. As explained in detailed in the impact plan, our project will include several networking activities which aim to the development of an exploitation strategy in direct contact with the stakeholders.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Ageing, Regenerative Biology, Stem Cells, Systems Biology
Research Priority	Systems Approach to Biological research
Research Initiative	ERASysBio plus (ERASysBioPlus) [2010]
Funding Scheme	X – not Funded via a specific Funding Scheme

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