The troubled immune system - molecular origins of immune dysregulation (360G-Wellcome-207556_Z_17_A)

Immune-mediated inflammatory disease is a major and increasing cause of ill health worldwide. Effective therapy is hindered by our incomplete understanding of immune regulatory mechanisms and how to manipulate them. In this research project, we will focus on the molecular dissection of early onset immune dysregulation as a means to identify relevant genes and pathways in an unbiased way. We will use next generation sequencing to uncover causative mutations in children manifesting autoimmunity, autoinflammation and lymphoproliferation, sometimes in a familial way. We will characterize the diseased immune system in fine detail, using state-of-the-art technologies to learn as much as possible from small volumes of patient blood and tissue. We will study the role of the encoded proteins in vitro, modeling the effect of mutations and exploring the associated immunobiology. Finally we will create and study knock-in mouse models in which hypomorphic patient mutations are precisely engineered into the homologous murine gene. By these means we will gain maximal mechanistic insight from these experiments of nature, improve diagnostic and therapeutic outcomes for our patients and empower the development of new and better approaches to therapy of other immune-mediated inflammatory diseases.