Omics interrogation of functionally competent hematopoieitic stem cells

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Project Summary/ Abstract Hematopoietic cell transplantation (HCT) is a life-saving treatment for disordered hematopoiesis, including ma- lignant and non-malignant diseases. Umbilical cord blood (CB) is a promising source of hematopoietic stem cells (HSCs) for HCT; however, CB HCT is limited by the low HSC numbers present in single CB units. Thus, there is a critical need to improve the functional competency and/or number of functional HSCs in each CB unit, and treatments to enhance HCT must be improved or supplemented with new treatments. The applicant's long-term goal is to establish himself as an independent investigator at an outstanding academic research in- stitution where his studies will focus on identifying ways to improve HSC function for enhanced HCT, with the goal of discovering novel therapeutic modalities to improve treatment for disordered hematopoiesis for im- proved patient outcomes. The investigator’s immediate career objectives are to successfully complete his post- doctoral training and transition to an independent investigator position. He will accomplish this by seeking guid- ance from expert mentors, improving his technical scientific skillset and developing career skills important to an independent investigator position. As an independent investigator, he will seek to provide insight into manners to improve HSC function using omics approaches supported with cell biology, biochemistry and mouse model- ling of HCT approaches. The goal of the associated research plan is to elucidate molecular programs that can be targeted to enhance CB HSC function and to generate sufficient preliminary data to submit a competitive R01 application in the final year of the award. Specifically, the research plan proposes examining combinations of treatments known to enhance HSC function for HCT, such as Dipeptidyl peptidase 4 (DPP4) inhibition and physioxic isolation of HSCs, to determine if these combinations are additive, synergistic, or have no further ef- fect. The proposed study will examine transcriptomic and epigenomic changes induced by treatments known to improve HSC function and the transcriptome of recently homed and early engrafted HSCs in a mouse model of HCT will be analyzed compared with the pool of cells transplanted to recipient mice. This data will yield insights into common and unique gene programs that are important for HSC function and engraftment. This study will provide candidate genes that can be targeted by inhibition or stabilization to improve HSC function and engraft- ment and will examine their importance using mouse models for HCT. Taken together, this approach will iden- tify new potential treatment modalities to enhance HCT. The applicant’s strong career development plan, guid- ance from his outstanding mentoring team, the environment at the internationally recognized top tier research institution of Indiana University School of Medicine, and completion of the proposed aims in the research ap- proach will prepare him for a productive and highly impactful career managing an academic lab focused on molecular mechanisms that can be exploited to improve patient outcomes for disordered hematopoiesis.