Macrophage identity as a function of cell of origin

PROJECT SUMMARY Macrophages exhibit remarkable functional heterogeneity and plasticity, reflecting their diverse developmental origins from yolk sac, fetal liver progenitors, or bone marrow. This diversity underpins their roles in tissue homeostasis and inflammation, with tissue-resident macrophages, primarily derived from yolk sac and fetal liver progenitors, involved in homeostatic tasks, and monocyte-derived macrophages from bone marrow driving acute inflammatory responses. Dysfunctions in these macrophage subtypes are linked to varying disease phenotypes, such as atopic dermatitis, graft vs host disease, arthritis, atherosclerosis, and Langerhans cell histiocytosis. The proposed research seeks to delineate the influence of ontogeny on macrophage specification and exploit this understanding to target dysregulated subsets in diseases like atopic dermatitis, Langerhans cell histiocytosis, and graft-vs-host disease. Building on preliminary findings that suggest distinct properties and developmental pathways for macrophages from fetal or adult hematopoietic stem and progenitor cells (HSPCs), and the identification of AHR as a key gene regulating TRM self-renewal, the study aims to selectively target and modulate these macrophage subsets. The approach encompasses culture-based methods, xenotransplantation, and genomic techniques, striving to unveil novel insights and therapeutic strategies for conditions driven by macrophage dysregulation. Dr. Katie Frenis is a 2nd year postdoctoral fellow who aims for a faculty position in the next 2 years. The work above is the cornerstone of the laboratory she hopes to build. Dr. Frenis is interested in the innate immune system, its heterogeneity, how the heterogeneity arises, and how it impacts disease across the age spectrum. She has a strong mentorship and collaborative network and aims to learn lab and budget management, grantsmanship, and administrative details before the R00 phase from her close mentors. Because of her career in teaching and publishing, she has extensive leadership and teaching/training experience and aims to leverage that into becoming a dedicated mentor. She will carry out her postdoctoral phase at the hematology/oncology department at Boston Children’s Hospital, which is a rich environment with a good atmosphere and a proven track record of producing faculty appointees.