THE NACHMANI LAB
RESEARCH PROJECTS
Cell-type-specific Ribosomes Control Hematopoietic Development
The ribosome was long viewed as a static, boring molecular machine, which is identical in all cells across an organism. However, evidence indicates that ribosomes exist as a heterogeneous population of complexes with distinct compositions and translation capacities. We study ribosome heterogeneity as a fundamental mechanism facilitating cell-type-specific translation programs that are essential for establishing and maintaining cellular identity.
Our work focuses on heterogeneity of ribosomal RNA modifications' landscape and how these shape ribosome function. Using a combination of advanced molecular approaches, genetic mouse models, and in-vivo experimental systems, we dissect ribosome diversity and function across the hematopoietic hierarchy.
The Malignant and Pre-malignant Ribosome
Ribosomopathies are a group of human genetic syndromes caused by mutations in ribosomal proteins. These patients frequently suffer from bone marrow failure, resulting from defective blood cell production, which is a major cause of morbidity and mortality. These patients also present with an increased risk of developing hematologic malignancies, including acute myeloid leukemia.
Our research aims to uncover the molecular and cellular mechanisms by which ribosome dysfunction drives bone marrow failure, promotes pre-malignant states, and ultimately contributes to leukemogenesis.
Exploring Translation as a Therapeutic Target for Leukemia
We are exploring new therapeutic opportunities by targeting the cellular translation machinery, a central regulator of gene expression and cell fate. Using genome-wide CRISPRi screens, we systematically identify components of the translational landscape that are essential for disease cell survival but dispensable in normal cells. By integrating these screens with clinically approved and experimental therapies, we uncover synthetic lethal interactions that reveal novel vulnerabilities.
Ribosomal Hijacking by Viruses
Pathogens, including viruses, hijack the host ribosome to promote their own replication and drive disease. We investigate the strategies viruses use to manipulate ribosome composition and function to meet their specific translational needs. Through these studies, we aim not only to deepen our understanding of viral infection but also to leverage viruses as powerful tools to uncover fundamental principles of ribosome function and translational control.
