ABSTRACT In this Pathway to Independence Award application, Dr. Christine (Ruochao) Zhang outlines detailed career developmental plans to strategically enhance her knowledge in trending hematology and her expertise of state- of-the-art techniques while interrogating how Dnmt3a mutations endow hematopoietic stem cells (HSC) a fitness advantage during chronic inflammation and prime defective hematopoiesis for disease progression. Dr. Zhang is a postdoctoral research associate at the Washington University School of Medicine and has a strong background in epigenetics and genetics with a diverse range of technical skills. Herein, she wants to understand how epigenetic perturbations lead to defective hematopoiesis and consequently blood diseases. The primary goal of Dr. Zhang is to become an independent investigator in epigenetic hematology. Dr. Zhang has proposed career development plans, where she will be rigorously trained with highly successful, world-renowned leaders in hematology, including hematopoietic stem and progenitor cell (HSPC) biology (Dr. Grant Challen), bone marrow niche and pathology (Dr. Daniel Link), and disease hematopoiesis (Dr. Timothy Ley). Her outstanding mentor team will ensure her success in reaching this ambitious goal. Dr. Zhang will gain 1) strengthened knowledge in HSPC biology, bone marrow composition, and hematologic disease pathology; 2) expertise in advanced epigenetic analysis at the single-cell level and in multiplex imaging analysis; 3) critical soft skills required for running a successful and innovative independent laboratory. Somatic mutations in DNA methyltransferase 3A (DNMT3A) acquired in the HSC compartment during aging give rise to clonal hematopoiesis (CH), a condition associated with increased risks of hematologic diseases. The disproportional prevalence between DNMT3A-CH (10%) and blood diseases (~1%) suggests environmental pressures are likely required for clonal selection and evolution for disease progression. While cumulative evidence has suggested that DNMT3A mutations can be selected by chronic interferon-gamma (IFNg) signaling, it remains elusive how DNMT3A mutations confer a fitness advantage to HSCs during chronic inflammation; how the expansion of Dnmt3a-mutant HSCs reshapes the bone marrow composition and ultimately leading to disease conditions. The goal of this study is to interrogate the mechanism(s) underlying the HSC fitness advantage conveyed by Dnmt3a mutations and to understand how the defective hematopoiesis selected by chronic inflammation gives rise to disease conditions at least in part attributed to bone marrow remodeling. The overarching goal of this proposal is to develop Dr. Zhang into a successful independent investigator in epigenetic hematology. The knowledge and experience acquired from the proposed studies and the career development plan will firmly set her on the path to becoming a leading investigator of epigenetic hematology.