Determining genetic mechanisms that drive in vitro hematopoiesis - PROJECT SUMMARY/ABSTRACT This proposal focuses on genetic determinants underlying human hematopoiesis, specifically the development of hematopoietic progenitor cells (HPCs) and their precursors. There is considerable interest in augmenting in vitro HPC production from cultured induced pluripotent stem cells (iPSCs), as this would support research and development of many blood cell-based therapies. To better understand genes and genomic loci that might improve in vitro blood cell yields, I used computational modeling to analyze blood trait genome wide association study (GWAS) data. I identified and validated Tropomyosin 1 as a gene that normally constrains in vitro production of HPCs and their endothelial precursor cells. In Aim 1 of this grant, I will determine mechanisms by which Tropomyosin 1 regulates HPC precursor development using well-defined in vitro iPSC culture models. In Aim 2, I will define other genes and genetic mechanisms that regulate HPC biology using novel adaptations of complementary statistical genetics approaches. The proposed five-year training program outlines development of my research career as an academic pediatric physician-scientist seeking to develop a research program investigating genetic mechanisms that regulate hematopoiesis. I completed an MD and PhD in cell and molecular hematology, pediatrics residency training, and am currently in my third year of fellowship training in neonatal and perinatal medicine at the Children’s Hospital of Philadelphia (CHOP). The proposed research will be carried out under the mentorship of Benjamin Voight, PhD, a leader in the field of complex human genetics; Stella Chou, MD, a leader in iPSC-derived hematopoiesis and transfusion medicine; and Deborah French, PhD, a leader in iPSC manipulation, hematopoietic culture, and blood cell biology. In addition, I am supported by an advisory committee composed of scientists and physician-scientists in relevant and complementary fields, who have together supported multiple K-award trainees. I have secured complete support from my institution, and will benefit from exceptional didactic training, extensive resources and core facilities, and world-class mentorship available at CHOP and the University of Pennsylvania for the duration of this award period. Training in an ideal academic environment, afforded by K99 support, will help me develop the skills required to become an independent physician-scientist studying hematopoiesis genetics during the R00 phase of this award. My goal is to run a laboratory that uses computational and biochemical approaches to understand genetic mechanisms and therapeutic strategies that enhance blood production. In this grant, I will obtain rigorous training in data science and hematopoiesis modeling. This will expand my repertoire of skills, propel my transition to independence, and increase my likelihood of success competing for R01 funding.
