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Asymmetric Distribution of Numb in
a stem cell undergoing division

The primary goal of our lab is to understand the signaling pathways that regulate the choice between stem cell renewal and commitment, and define how the same signals are subverted in cancer. These studies have implications not only for understanding the basic mechanisms that regulate normal and oncogenic self-renewal, but also for enhancing stem cell based therapies for human disease.

Developmental Signaling in Stem cells and Cancer
We have focused in large part on developmental signals such as Wnt, Notch and Hedgehog which are critical regulators of normal  development in a variety of systems, and a major target of mutation in human cancer. Our research using knockout and transgenic approaches suggests that these signals are activated in hematopoietic stem cells, and that they functionally contribute to stem cell self-renewal in vivo.  In addition our data also shows that inhibition of these signals can block leukemia development and propagation in mouse models of the disease. Our current work is focused on further understanding  the relationship between these pathways at a molecular level and also defining the role of these signals in human leukemias.

Stem Cell Regeneration after Injury
Besides renewing at a basal rate to replenish the blood during homeostatic conditions, stem cells also have the capacity to rapidly regenerate and repair the hematopoietic system after injury. However little is known about the signals and mechanisms that regulate regeneration. Using models of regeneration based on delivery of chemotherapeutic agents and radiation we have begun to define the microenvironmental changes that occur after damage and are sensed by stem cells to initiate the renewal process. Additionally, we are also investigating the intrinsic genetic program activated within stem cells that allows regeneration to occur. These studies will provide the basis for developing new approaches to accelerate regeneration after injury.

Imaging
A major focus of our research is to image stem cell growth, regeneration and transformation in real time.  Ultimately this will be the most powerful approach to understanding how regeneration and oncogenesis occur in the body so that we may design better ways to activate or block these processes when needed.  We use state of the art in vitro and in vivo imaging technologies to visualize stem cells interacting with the microenvironment, and defining the consequences  of these interactions on normal cell fate decisions and oncogenic cell growth.

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