Proteotranscriptomic regulation of homing and engraftment in hematopoietic stem and progenitor cells for hematopoietic cell transplantation

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Project Summary/ Abstract There is a strong need to improve the functional capacity of hematopoietic stem cells (HSCs) and progenitor cells (HPCs) derived from human umbilical cord blood (CB) to enhance the efficacy of hematopoietic cell transplantation (HCT) for the treatment of disordered hematopoiesis. However, few studies have focused on defining the global protein and gene programs involved in regulating HSC and HPC homing to and engraftment in the bone marrow in order to identify therapeutic targets to improve HCT. The research proposed in this application will examine the global protein targets of and global gene programs dependent on Dipeptidyl peptidase 4 (DPP4), a regulatory serine protease that plays important roles in hematopoiesis and HCT. Previous work by our lab has demonstrated that DPP4 inhibition has clinical utility by enhancing CB transplantation for patients with disordered hematopoiesis, though this DPP4 inhibition must be applied at high doses to observe modest effects on CB HCT. Thus, fully understanding the targets of DPP4 and the gene programs affected by inhibiting DPP4, which leads to improved HCT, will allow for elucidation of molecular mechanisms to target therapeutically, either by targeting pathways downstream of DPP4 for improved efficacy or by identifying pathways that can be targeted in combination with DPP4 for further enhancement of HCT. Further, the proposed study will examine gene programs enriched in specific subpopulations of HSC and HPC that can efficiently home to the bone marrow utilizing multi-modal single cell RNA-sequencing technology that will allow us to define cells by both their cell surface protein expression and their transcriptome. Analysis of gene programs that are enriched in HSC and HPC that can home to the bone marrow of immune deficient mice will allow for elucidation of gene programs that can be targeted by inhibition or stabilization to enhance homing, allowing for novel therapeutic manners by which to enhance HCT. The goal of this research plan is to elucidate novel mechanisms that can be targeted to enhance homing and engraftment of CB HSCs and HPCs. The investigator's long-term goal is to provide insight into novel manners by which to improve HCT therapeutically for overall improvement of treatment for disordered hematopoiesis. Successful completion of the research plan and career development plan outlined in this fellowship application will allow the applicant to develop expertise in 1) analyzing complex proteomic, transcriptomic, and multi-modal omic data sets, 2) using these data to develop novel approaches to improve homing and engraftment of HSCs and HPCs and to understand hematopoietic regulation, and 3) testing the effects of genetic manipulations or drug treatments on HCT. This will prepare the applicant for a productive career managing an academic lab focused on molecular mechanisms that can be exploited to improve patient outcomes for disordered hematopoiesis using next generation sequencing, proteomics, basic cell biology and biochemistry, and mouse modelling approaches.