Trista Regenerative medicine holds great promise to alleviate morbidity and mortality in patients suffering from organ failure. Pathways that govern stem cell behavior and organ development can be modulated to affect adult organ repair and regeneration. Our laboratory focuses on developmental hematopoiesis as a key to uncovering general principles of stem cell function, self-renewal and tissue regeneration. Hematopoietic stem cells (HSCs) give rise to each of the blood lineages found in the adult vertebrate; the gene programs regulating HSC development and homeostasis are highly evolutionarily conserved. We are using the zebrafish as a model system to discover novel regulators of HSC formation. In addition, we employ murine models to document evolutionary conservation of these signaling pathways during development and in hematopoietic regeneration following injury or transplantation. Through a chemical genetic screening approach, we identified several novel compound modifiers of blood stem cell formation; each pathway isolated in the screen altered the normal expression pattern of the conserved HSC marker runx1. This methodology led to the first example of FDA approval for the investigational use of a compound identified in an unbiased screen in zebrafish for clinical application in the treatment of human disease. Our laboratory will use both chemical and genetic approaches in the zebrafish to characterize novel mechanisms controlling HSC induction in the vertebrate embryo. Additionally, through comparative genomic examination of zebrafish and murine sites of embryonic hematopoiesis, we aim to decipher regulatory networks that are central to HSC formation and function. Using chemical ablation, irradiation injury and transplantation approaches, we will further define the functional conservation of HSC regulators identified in the embryonic screens in controlling adult marrow homeostasis in zebrafish and mice. Xenotransplantation experiments using human cord blood with be employed to investigate translational potential. The work in our laboratory has direct relevance for the development of novel therapeutic strategies for controlling leukemogenesis and enhancing stem cell transplantation biology.

Wolfram Developmental signaling pathways govern the formation and function of stem cells, thereby holding the key to unlocking the promise of adult tissue regeneration, and to inhibiting cancer development. In our laboratory, we use zebrafish as the primary model to study the liver and explore the regulation of endodermal progenitor cell specification, organ differentiation and growth. We then examine the conserved role of these signaling pathways in regulating tissue growth in surgical and chemical models of liver regeneration and genetic liver cancer models. We also use murine liver injury models to demonstrate evolutionary conservation and relevance for human disease. Our prior work has shown that we can translate our findings from the fish tank to the bedside, as the first clinical trial originating from our findings in the fish has begun to enroll patients. We have found that the wnt pathway is an important regulator of liver development and regeneration. Recently, we showed that prostaglandin signaling interacts with wnt, offering a chance to therapeutically modify wnt-mediated stem and progenitor cell growth. In an effort to identify new pathways and genes important for liver development, we performed a genetic screen and characterized several mutants with disturbed liver formation. In addition, we are proceeding with a chemical genetic screen to characterize regulators of liver growth. We aim to use these findings and genomic analyses of clinical cohorts to better understand the interaction of regulatory signals that affect liver function and regeneration. The work in our laboratory is directly relevant for developing new treatment options for patients with liver failure and liver cancer.