Doctor of Philosophy (PhD)
Molecular Genetics & Cell Biology
Dr. Kyle J. Hewitt
Red blood cells (RBCs) essential for tissue oxygenation are generated by the process of erythropoiesis. Any decrease in the RBCs or the oxygen-carrying molecule hemoglobin leads to anemia, affecting nearly 1.62 billion people worldwide. Stress erythropoiesis describes the process of accelerating RBC production during anemia, to compensate for the loss. Among several important mediators of stress erythropoiesis, paracrine signals - involving cooperation between Stem Cell Factor (SCF)/Kit signaling and other signaling inputs – are required for the activation/function of a unique population of progenitor cells - stress erythroid progenitors (SEPs). Biological mechanisms controlling SEP activation and function can be distinct from developmental and steady-state drivers of erythropoiesis, representing attractive therapeutic targets to resolve acute and chronic anemia.
Prior work revealed that the Sterile Alpha Motif (SAM) Domain 14 (Samd14) gene is transcriptionally upregulated by GATA binding transcription factors via an intronic enhancer (Samd14-Enh) in a model of acute hemolytic anemia induced by the RBC-lysing chemical phenylhydrazine. Mouse knockout of Samd14-Enh (Samd14∆Enh/∆Enh) established that the Samd14-Enh is dispensable for steady-state erythropoiesis but is required for recovery from severe hemolytic anemia. SEPs from Samd14∆Enh/∆Enh also exhibited defective SCF/Kit signaling during recovery from anemia. Thus, we hypothesized that following anemia, erythroid recovery was promoted by SAMD14 mediated cell signaling in stress erythropoiesis.
My dissertation research discovered a new mechanism that has revealed that SAMD14 promotes Kit signaling and stress progenitor activity ex vivo, facilitated by its SAM domain. In addition, we found that SAMD14 interacts with α- and β heterodimers of the F-actin capping protein (CP) complex via a unique CP binding (CPB) domain in SAMD14. This revealed distinct mechanisms of SAMD14 dependent signaling in two essential erythropoiesis promoting pathways, mediated by SCF and erythropoietin (Epo), with the SAMD14-CP interaction being required for SCF signaling but dispensable for Epo signaling.
Together these studies and additional preliminary studies of a SAMD14 dependent phosphoproteome, indicate a mechanism for SAMD14 function, whereby it acts as a mediator in multiple signaling pathways activated in response to SCF and Epo, two cytokines essential for stress erythropoiesis and anemia recovery.
Ray, Suhita, "SAMD14 Mechanisms in Stress Erythropoiesis" (2023). Theses & Dissertations. 767.
Available for download on Friday, August 01, 2025