The ASPIRE Path in Molecular Medicine

Splicing, the process by which introns are removed from pre-mRNA, is coordinated by machinery called the spliceosome. Mutations in spliceosome components and associated proteins have been linked to many pathologies, but are particularly prevalent in myeloid neoplasms, with over 50% of patients with myelodysplastic syndrome possessing a splicing factor mutation. Recent work has also begun to characterize splicing as a key regulatory node of the innate immune response. Given the altered immune and inflammatory responses observed in patients with hematological cancers, my goal is to uncover mechanisms by which mutations in splicing factors may contribute to this immune dysregulation. My project is well-suited for the APMM, as it addresses a basic science question regarding the ability of splicing to regulate the immune response, and uses this to identify potential therapeutic targets to promote positive outcomes for cancer patients. By participating in the APMM and potentially integrating human subjects into this project I would be able to observe how these mutations may correlate with altered immune responses in patients, better understand the prevalence of these mutations, and couple data from human subjects with my in vitro and murine in vivo data to significantly enhance the clinical relevance of my findings.