Elucidation of the Molecular Mechanisms of Mastocytosis

Mastocytosis is a myeloproliferative disease characterised by the accumulation of neoplastic mast cells in one or several organs that can result in organ failure. The majority of adult patients with mastocytosis present with systemic mastocytosis (SM) defined as mast cell accumulation in one or more visceral organs and the prevalence is one in 364,000 in Europe.

Around 80-90% of patients harbour a somatic activating mutation in the c-KIT gene (D816V). The D816V mutation results in the constitutive activation of the c-Kit receptor causing the activation of multiple signalling pathways resulting in an increased proliferative and survival advantage of the mast cell lineage, rendering the cells resistant to Imatinib. Despite advances in the understanding of myeloid neoplasia the aetiology of mastocytosis is poorly understood. The presence of the c-KIT mutation does not explain the heterogeneous clinical behaviour of the disease.

We will use new and emerging technology platforms specifically designed for high resolution data-independent acquisition (DIA) and molecular techniques to elucidate the molecular mechanisms involved in Mastocytosis.

We will carry out both a global and targeted analysis of the proteome/kinome of isolated progenitor cells from the bone marrow of SM patients and compare these to control subjects using DIA (SWATH and Waters novel MSe and 2D-MS). In a single measurement, these techniques capture all of the components in a biological sample -a digital proteomic map. The top candidates identified as having significance in mastocytosis pathogenesis will be further validated in functional molecular biology studies.

Our proposed work programme will produce permanent digital maps allowing the investigation of disease processes using patient specific disease models to gain a better understanding of the processes underpinning the disease in the correct context. These models can be used in the development of new interventions to treat disease.

Qualifications
Applicants should already hold a minimum upper second class undergraduate degree (or equivalent) in a relevant science-based degree and/or a Masters degree in a relevant subject. Experience in molecular biology/oncology/proteomics/biomedical science is desirable.

The supervisory team for this project will include Dr Robert Graham (University of Manchester), Dr Ciaren Graham (Manchester Metropolitan University) and Professor Paul Townsend (University of Manchester).