Mapping the genetic and cellular basis of human DC haematopoiesis. (360G-Wellcome-101155_Z_13_C)

Hypothesis: Human DC haematopoiesis is regulated by specific genetic factors that govern the development of precursors with restricted DC potential, giving rise to peripheral DCs independently of monocytes. Objectives: 1.To identify genes of clinical importance regulating human DC haematopoiesis in vivo. I have shown that DC deficiency syndromes provide a powerful means of analysing the genetic factors that control DC development in vivo. I will further screen and characterise new genetic causes of DC deficiency. 2.To identify human progenitors and precursors with restricted DC potential. DC precursors identified in the mouse have no known human homologues. I aim to solve this problem using transcriptomic profiling to identify and separate precursors with true DC potential from those with monocyte potential (that subsequently form mo-DCs), comparative transcriptomics to discover new cross-species markers of DC precursors and single cell progenitor studies to track monocyte- independent DC potential. 3.To define the intrinsic effects of genetic mutation on discrete stages of DC development. I will use CD34+ progenitors or induced progenitor stem cells from patients with DC deficiency to determine how genetic mutation interrupts discrete stages in DC development, thus integrating the genetic and cellular maps of DC homeostasis.