Len Harrison-Projects

Len Harrison-Projects


Epigenetic regulation of T-cell function in health and disease

We have demonstrated differential microRNA (miR) expression and DNA methylation between human T cell subsets, and differences in these epigenetic signatures in naïve and natural regulatory T cells (nTreg) between healthy and T1D at-risk individuals. These studies have revealed new disease markers and mechanisms (e.g. genes that regulate T-cell function; Ezh2 methyltransferase function in T-cell differentiation) and are being extended to other immune disorders. This project comprises one or more sub-projects: 1) identifying the roles of specific genes that are differentially methylated in FOXP3 binding regions in nTreg, in healthy individuals and those with or at risk of immune-inflammatory diseases including T1D; 2) identifying changes in epigenetically modified genes during the development of T1D, and environmental factors that drive these changes, in conjunction with microbiome, metabolome and immunome studies; 3) defining the functions of Ezh2 and other PRC2 components in T-cell differentiation.

Team members: Yuxia Zhang, Gaetano Naselli, Len Harrison

CD52-Siglec interactions in health and disease

The role of CD52, a cell surface GPI-anchored glycoprotein, was unknown (except as a target of the CAMPATH monoclonal antibody) until we showed that activated T cells release soluble CD52 to mediate immune suppression by binding of its glycan to Siglec receptors. Binding requires co-interaction with the danger-associated molecular pattern (DAMP) molecule HMGB1.

This project comprises one or more sub-projects: 1) structure-function analysis of CD52-HMGB1-Siglec interactions in T cells and other immune cells, including X-ray crystal structure and glycan composition; 2) defining intracellular signaling pathways that mediate CD52-induced cell suppression and cell death; 3) in vivo studies of CD52-Fc including its therapeutic effects in laboratory models of immune-inflammatory disease (T1D, arthritis, encephalomyelitis, bowel disease, sepsis); 4) defining the immunosuppressive role of CD52 in the reproductive tract.  

Team members: Maria Esther Bandala-Sanchez, Alana Neale, Katrina Ngui, Natalie Stone, Len Harrison

Does inflammation cause insulin resistance and type 2 diabetes (T2D)?

Over the last decade numerous laboratory studies have shown that obesity is associated with inflammation in adipose tissue and that agents that target this inflammation are therapeutically effective. Nevertheless, despite several clinical trials these agents have not been effective in humans with T2D. To identify novel therapeutic targets, we isolated inflammatory factors released from human adipose tissue. We have identified a factor that causes diabetes-like changes in cultured human fat cells. This project aims to define the mechanism of action of this factor and demonstrate that its inhibition prevents the development of insulin resistance and diabetes in laboratory models.

Team members: John Wentworth, Katrina Ngui, Len Harrison