Genetic mouse models have been a powerful system to delineate key mechanisms of cancer development. However, there are likely to be gene expression and regulation differences between mouse and man that affect the applicability of some findings in these models. Furthermore, the inbred strains that are used may come with additional genetic caveats due to loss of heterozygosity. For these and other reasons, many cancer studies that identify targets or mechanisms in mouse systems benefit from replicating key findings in a relevant human cell model. Xenograft technology has advanced significantly over the past decade. There has been a rapid proliferation of immunodeficient mouse strains, each with specific strengths relative to each other. More sophisticated in vivo studies are now possible as a result of these new strains and many other technical advances in sample processing, detection, analysis and modeling of therapeutic interventions. However, these mice are difficult to breed and manipulate due to their immunodeficient status. Human cells also require a different set of considerations. Human hematopoiesis in this environment is very different from what is found in mouse transplant systems. There are additional host versus graft and graft versus host issues to consider. Human cells require different culture conditions and transduction protocols. Human cells are morphologically distinct. The markers used for detection are very different, making flow cytometry experiments much more involved. I have spent the last 13 years working on these models and have made several improvements along the way. My ability to apply my experiences to the projects of many NCI funded investigators through the xenograft core facility that I have built adds significant efficiency and value to the science that can be done at our institution. This proposal is in alignment with new NCI initiatives to use mouse models and genomics to identify new molecular mechanisms of carcinogenesis, delineate mechanisms of resistance, and identify new targets for drug discovery and development.
There are significant technical hurdles in the way of investigators wishing to employ xenograft models of various hematopoietic cancers. I have built a comprehensive, full service core resource based on my extensive experience in the field that is available to all investigators at Cincinnati Children's Hospital and beyond. This proposal will add much needed stability to this core and ensure that the many NCI funded investigators and projects at our institute continue to realize the benefits that stem from this specialized expertise.
