Physiological and pathophysiological roles of DARC (ACKR1) in haematopoiesis (360G-Wellcome-200817_Z_16_Z)

We aim to study the previously unrecognised contribution to haematopoiesis made by the atypical chemokine receptor 1 (ACKR1; also known as Duffy Antigen Receptor for Chemokines or DARC). Our initial data show that DARC is expressed by nucleated erythroid cells and that mice, which lack DARC selectively on erythroid cells, have profoundly altered bone marrow (BM) parameters as compared to wild type mice. Over the next five years, we will discover the mechanisms by which DARC expression on erythroid cells affects: i) steady-state haematopoiesis and the molecular make-up and functional profiles of BM stem-, progenitor- and lineage restricted cells; and ii) diseases that rely for their pathogeneses on haematopoietic cell outputs, notably glomerulonephritis, prostate and breast cancer and anti-microbial host defence. We will correlate our findings in experimental mouse models with molecular and cellular parameters of haematopoiesis in individuals of West African origin who carry the common FyB(ES) polymorphism and thus selectively lack DARC in the erythroid lineage. FyB(ES) is the most predictive ancestry-informative marker of African origin and individuals with FyB(ES) are recognised to have altered incidences and outcomes of several debilitating diseases compared to other DARC polymorphisms. Our research seeks to provide a causative explanation for these findings.