Pathophysiological mechanisms of JAGN1-associated severe congenital neutropenia

• Applicants: Maksim Klimiankou, Ph.D.; Professorin Julia Skokowa, Ph.D., since 11/2022
• Subject Area: Hematology, Oncology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 491561957

Mutations in the JAGN1 gene cause severe congenital neutropenia (CN), a pre-leukemic bone marrow failure syndrome, which is characterized by impaired neutrophil differentiation. JAGN1 encodes an endoplasmic reticulum (ER)-resident protein which is conserved in metazoans, however, its function is poorly understood. Also, the mechanisms by which JAGN1 mutations affect the maturation of neutrophilic granulocytes are largely unclear. In this research proposal, we have successfully established a patient-derived induced pluripotent stem cell (iPSC) model for JAGN1-associated neutropenia and developed jagn1-deficient zebrafish, which display impaired neutrophil development. We aim to combine these cellular and animal models to study the pathophysiological mechanisms of JAGN1-associated CN. In objective 1, we will determine the effect of JAGN1 mutations on unfolded protein response (UPR) and ER stress, as a possible mechanism that can lead to CN.In objective 2, we will elucidate the effect of JAGN1 mutations on G-CSFR signaling, the main pathway involved in steady-state and emergency granulopoiesis.In objective 3, we will explore the role of JAGN1 mutations in hematopoiesis independent organ abnormalities of Jagn1-CN patients.A comprehensive molecular understanding of the JAGN1 function is key to define the mechanisms by which JAGN1 mutations lead to CN and is the first step towards our ultimate goal, which is the development of new therapeutic strategies for JAGN1-associated CN patients who showed no or poor response to the granulocyte colony-stimulating factor treatment, which is still the only available treatment for CN.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Baubak Bajoghli, until 11/2022