Transcriptional control of multinucleated giant cells and osteoclasts. (360G-Wellcome-087264_Z_08_Z)

£316,007

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