Genomic system biology approaches offer new aspects to understand the basis of diseases and to develop new therapeutic strategies. Here, we propose to study rare human variants of the immune system to provide novel explanations of mechanisms governing inflammation and leukemogenesis. Following a full circle of translational research, our group has previously defined several novel clinical entities and elucidated their molecular defects (Nat Med 2007, NEJM 2009). Further studies have highlighted the critical role of new pathways for general biological principles (Immunity 2005, Nat Gen 2007, Nat Med 2008). Finally, we have developed innovative gene and cell-based therapeutic strategies and tested their feasibility in clinical trials (JCO 2007, NEJM2009).The overall goal of ¿Explore¿ is to decipher novel pathways controlling myeloid cell function and leukemogenesis. The following specific aims are proposed:1. To elucidate genetic defects causing neutrophil disorders in children by homozygosity mapping and to perform functional studies in vitro and in vivo using relevant animal models2. To identify novel genes controlling endoplasmic reticulum cell function and the secretory pathway in myeloid cells by employing RNA-interference technology3. To define the role of novel factors involved in controlling the topology of the endoplasmic reticulum and ER-stress in murine model systems4. To study the role of HAX1 in hematopoisis and leukemogenesis using a new murine HAX1flox allele and to develop a clinical gene therapy approach for patients with severe congenital neutropenia due to HAX1-deficiencyThese studies will not only identify novel genetic factors controlling human immunity and leukemogenesis, but may ultimately impact on the development of novel therapeutic strategies.