Matthews, Sharon

I studied at the University of Birmingham, receiving a BSc (Hons) degree in Medical Sciences in 1995.  I carried out my PhD research at the Cancer Research UK laboratories (London), working with Enrique Rozengurt and Doreen Cantrell on the serine/threonine protein kinase PKD. During this time I developed an interest in signal transduction pathways and how they regulate lymphocyte development and function and from 2000-2003, I was a postdoctoral research fellow working with Andrew Scharenberg at the Beth Israel Deaconess Medical Center, Harvard and the University of Washington, investigating the function of diacylglycerol-regulated protein kinases and novel ion channels in immune cells. I then returned to the UK to work with Doreen Cantrell (University of Dundee) on immune cell signalling, supported by a Royal Society Dorothy Hodgkin Research Fellowship.  In 2007 I was offered a position as an Immunology Lecturer at the University of Dundee and I am currently based in the Division of Cancer Research, within the University’s Medical Research Institute.  My research goals are to understand the complex molecular mechanisms that underlie normal (and thus pathological) lymphocyte development and function, supported by funding from the Leukemia Research Foundation, the Royal Society, Tenovus Scotland and a Cancer Research UK Career Establishment Award.

B cells are the antibody-producing cells of the immune system but they also function as antigen presenting cells and are an important source of regulatory cytokines.  Specific receptor-ligand interactions, signaling pathways and gene expression programs are essential for normal B cell development and function.  However, the expression and/or function of many of the molecules involved in these cellular processes are defective in cancer and in autoimmune and immunodeficiency diseases.  Our research focuses on understanding the precise molecular mechanisms that regulate normal B cell development, using a variety of biochemical, cell biological and in vivo experimental approaches. Knowledge in this area will increase our understanding of the causes of B cell-mediated diseases and will aid in the identification and development of novel biomarkers and treatment strategies for them.

In particular the lab is interested in:

• The role of monocye enhancer factor 2 transcription factors and class IIa histone deacetylases in regulating lymphocyte development, trafficking and function.
• The role of Protein Kinase D enzymes in the innate and adaptive immune systems.

Class IIa histone deacetylases and lymphocyte biology

Class IIa histone deacetylases (HDACs) are key regulators of differentiation and development in many cellular systems and are regulated by reversible serine phosphorylation events that control their subcellular localization.  Unphosphorylated, nuclear-localised class IIa HDACs function as transcriptional repressor proteins and are targeted to specific gene loci by interactions with certain DNA-binding proteins.  Phosphorylation of class IIa HDACs in response to specific signals results in their accumulation within the cytoplasm and de-repression of target genes.  We have identified a novel antigen receptor-regulated signaling pathway, whereby PKD kinases play an essential role in regulating class IIa-HDAC phosphorylation and nuclear exclusion in antigen-receptor activated B-cells.  Currently, we are investigating the biological functions and gene targets of class IIa HDACs in primary mammalian B cells (and other leukocytes).  The aim of these studies is to understand the regulation, biological functions and mechanisms of action of specific HDAC family members in normal and pathological immune settings.

The role of Mef2 transcription factors in lymphocyte development and function

Monocyte enhancer factor 2 (MEF2) are a family of DNA binding proteins that recruit histone modifying enzymes, including class IIa HDACs and histone acetyltransferases, to repress or enhance gene transcription respectively.  Mutations within MEF2B and MEF2D family have recently been identified in human B cell malignancies but the mechanisms by abnormal MEF2 transcriptional activity drives malignant B cell transformation is unclear. In collaboration with Prof. Simon Arthur (College of Life Sciences, University of Dundee), we are currently investigating the role of Mef2 family members in lymphocyte development and function. 

Protein Kinase D function in leukocytes

Mammalian Protein Kinase D (PKD) isoforms have been implicated in the regulation of diverse biological processes in response to diacylglycerol and Protein Kinase C (PKC) signaling. PKD2 is the dominant isoform expressed in lymphocytes but its expression and catalytic activity is not required for the development of mature, peripheral T and B cells.  PKD2 catalytic activity is however required for efficient antigen receptor-induced cytokine production in T cell and for optimal T cell–dependent antibody responses in vivo.  We are now extending these studies to determine the biological roles of PKD enzymes in other leukocytes, including B cells and myeloid lineage cells.

I currently teach on undergraduate Immunology modules for 1st year M.B.ChB. Medical students and for 3rd and 4th year (Hons) B.Sc.and B.M.Sc. students.  I also contribute to other teaching for Medical students (Year 1 Student Selected Component essays; Year 3 Transition block) and Dental students (Year 1 Immunology component).

I supervise Ph.D and Masters students in my laboratory and also supervise and examine research projects carried out by B.Sc.(Hons)/B.M.Sc. undergraduates.