Dr George Bou-Gharios

Current areas of research

Three areas of investigations are currently being pursued in the lab:

Determination of critical sequences in collagen type I gene promoters

Collagen type I is produced by several cell types during development and in response to injury in adult tissue. Results from our laboratory suggests that this expression is controlled by an enhancer, termed far upstream enhancer since it is located some 17 kb away from the transcription start site. The shortest sequence, which confers the full expression is a 1.5kb. sequence is characterised by the presence of three DNaseI hypersensitive sites which are required for the activity of this enhancer. The hypersensitive sites are present in cells that synthesise collagen but not in cells that do not express these genes. More recently, we have also determined that this enhancer is evolutionary conserved between mouse and human however the role of the hypersensitive sites may be different in the two species. Since the enhancer drives the reporter gene expression in different types of cell, we are seeking to determine the critical sequences that drive expression in any given cell lineage.

Understanding the molecular and cellular events leading to fibrosis in connective tissue diseases

We are using the transgenic approach we developed above to target the processes and cells that are involved in the progressive, degenerative diseases affecting connective tissues (fibrosis) which currently pose insurmountable problems in terms of clinical management.  In addition to the genetic and social disorders (such as excessive alcohol consumption leading to liver cirrhosis), post-surgery scarring, renal disease and systemic fibrotic conditions are associated with very high cost both in medical treatment and loss of earnings. The individual diseases, may be rare but collectively they present a large number of cases.  For most of these diseases, there is currently no effective proven therapy. Development of efficient technologies for the identification and genetic manipulation of the central cell type that is heavily involved in connective tissue deposition, the fibroblasts, is a definite step in development of targeted therapeutic modalities for fibrotic diseases. 

Identification of master regulatory factors in mesenchymal cells differentiation into the fibroblast lineages

Fibroblasts provide crucial structural components in almost all organs, are centrally involved in tissue repair and are pivotal in many disease processes, including cirrhosis of the liver, lung fibrosis and progressive scarring in the kidney.  In contrast to other cell types derived from mesenchymal progenitors, the transcriptional mechanisms that result in fibroblast characteristics have not yet been elucidated. For other cell lineages such as myoblasts,chondrocytes, osteoblasts and lipocytes, specific sets of master transcription factors have been identified which are central to commitment and differentiation.

A challenge in understanding fibroblast differentiation and behaviour is that in normal adult tissues these cells are relatively quiescent with identification being based on morphology, location, and absence of markers of other lineages.  We are therefore focusing on embryonic fibroblasts, which are characterised by high levels of expression of type I collagen. Previous experiments have clearly established that specific cis-acting regions direct expression of COL1A2 in different mesenchymal populations in late embryonic development.