Transcriptional control of multinucleated giant cells and osteoclasts. (360G-Wellcome-087264_Z_08_Z)
Macrophages are able to fuse and differentiate into either multinucleate giant cells (MGCs) at sites of chronic inflammation or osteoclasts within the bone. However, the molecular mechanisms that control this developmental process remain elusive. We utilize a tractable cellular system for analyzing the gene regulatory networks that underlie macrophage differentiation. By genome wide expression analysis we identify the Hic-5 nuclear co-activator as transiently induced during macrophage developm ent. Targeting of Hic-5 by shRNA diverted macrophage precursors to differentiate along the MGC cell fate. Ectopic expression of Hic-5 within bone marrow derived macrophages resulted in the loss of osteoclast development. By these loss and gain of function approaches we demonstrate Hic-5 as a novel cell fate determinant in repressing the MGCs and osteoclasts cell fates during macrophage development. As Hic-5 binds to DNA indirectly, through protein-protein interactions, we propose to use ChIP-S eq in conjunction with bio-informatics to identify this protein partner. Secondly, we shall establish the requirement of Hic-5 for the development of macrophages by the generation of mice containing a conditionally floxed Hic-5 allele. The accomplishment of these research aims will be of fundamental importance in the greater understanding in the pathology of chronic inflammation and bone disorders.
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Grant Details
Amount Awarded | 316007 |
Applicant Surname | Laslo |
Approval Committee | Molecules, Genes and Cells Funding Committee |
Award Date | 2009-02-25T00:00:00+00:00 |
Financial Year | 2008/09 |
Grant Programme: Title | Project Grant |
Internal ID | 087264/Z/08/Z |
Lead Applicant | Dr Peter Laslo |
Partnership Value | 316007 |
Planned Dates: End Date | 2012-09-27T00:00:00+00:00 |
Planned Dates: Start Date | 2009-09-28T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | Yorkshire and the Humber |