*EASTBIO* Senescence and aging in the haematopoietic system: Impact of interferon γ on the differentiation and survival of early haematopoietic progenitors during life

Our body has to constantly replenish cells of the blood system. At the same time the haematopoietic system shows evidence of aging, which is associated with increased incidence of myeloid malignancies, myelodysplasia, and multifactorial immune dysfunction. To further our understanding of the complex interplay between the blood system and the environment, this project is centered on the impact of signaling by proinflammatory cytokines in the ageing of haematopoietic progenitors.

Interferon γ (IFN γ) is a critical element in innate and adaptive immune responses against viral and intracellular bacterial infections. Most importantly, IFN γ as well as IFN α/β have been shown recently to be involved in the control of dormancy versus proliferation in haematopoietic stem cells (HSCs) [1, 2]. Extending these studies we have reported recently that IFN γ is also a key modulator of early haematopoiesis [3]. However the exact mechanistic role of IFN γ in these early compartments is still poorly understood.

The current project will have four objectives:

• Analysis of the functional role of IFN γ in the ageing process of early haematopoietic progenitors.

Our focus will be on the purification of HSCs and haematopoietic progenitors using multiparameter flow cytometry in wild type as well as IFN γ signalling-deficient animals to enable further functional and genetic experiments. In parallel we will analyse turnover and life span of stem cells and multipotent progenitor subsets both in vitro and in vivo. We will employ a novel animal model established in the lab, which allows the inducible deactivation of individual components of the IFN γ signalling pathway. Advanced mathematical modelling will be used to gain insights into the population dynamics comparing the various animal models.

• Investigating transcriptional networks in selected progenitor populations.

Building on the refined resolution and isolation of stem cells and haematopoietic progenitors we will generate genome-wide, stage-specific datasets of their respective transcriptional activity and epigenetic modification of their DNA. These dataset will be used to investigate the link between the genetic phenotypes, functional potential and ageing.

• Effect of IFN γ on haematopoietic compartmentalisation and cellular niches.

We will investigate the composition of the bone marrow niches, which are supporting stem cells and progenitors throughout the life. Our main focus is the outcome of changes in niche numbers affecting the subsets of immune-competent cell over the life span of the animal and the effect of IFN γ on the senescence of the stromal compartment.

• What is the impact of ageing on immunosurveillance?

Haematopoietic progenitors are to some extent involved into the immunosurveillance which depends on the mobilisaton of these cells out of the bone marrow and re-entry. Results from the three objectives above will be analysed for the age-related changes of this process.

This exciting PhD project will employ a variety of techniques cell biology (cellular lifespan and population turnover, molecular biology (analysis of transcriptional networks) and biochemistry (signalling pathways). In addition, we will utilise cutting-edge technology in flow cytometry, imaging (confocal microscopy) and 3D image reconstruction. The combination of these technologies provides an ideal environment for interdisciplinary training in a challenging project at the interface of immunology and stem cell biology.

Lab web site url: http://www.crm.ed.ac.uk/research/group/haematopoietic-stem-cells-and-leukaemia