Project Details
Projekt
Exploring the potential to restore cellular homeostasis in clonal hematopoiesis and immunity
Applicant
Dr. Mirco Friedrich
Subject Area
Hematology, Oncology
Cell Biology
Cell Biology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 512475649
Cellular homeostasis is disrupted by aging and disease. Young cells maintain a balanced proteome by effectively removing misfolded proteins and are epigenetically competent to regenerate. Aging is accompanied by an imbalance of the proteome due to inefficient removal of proteins, misregulated transcription, and loss of relative stoichiometry of protein complexes. Clonal hematopoiesis (CH), which causes epigenetic perturbation of immune cells, is used as a model for impaired homeostasis. Cell type-specific cyclic pulsing of the Yamanaka factors Oct4, Sox2, Klf4, and c-Myc (collectively referred to as OSKM) is thought to serve to restore affected cells to a more youthful state in which they are putatively more proteostatically and epigenetically resilient. The epigenetic and proteostatic changes associated with introducing Yamanaka factors will be characterized and candidates will be identified that can be directly modulated to develop a refined therapeutic. This therapeutic will be applied using a newly developed RNA-based trans-splicing approach to target the affected cell types in vivo. This project will address impaired cellular homeostasis in myeloproliferative diseases and immunity, providing solutions to timely and critical questions in biomedical research. Restoring cellular homeostasis in specific cellular contexts without loss of cell fate has the potential to enable researchers and clinicians to identify, test, and genetically engineer context-sensitive therapeutic approaches for patients with a variety of degenerative diseases and premalignant conditions, and is thus aligned with translational medicine and genome engineering.
DFG Programme
WBP Fellowship
International Connection
USA
