One of the first somatic stem cells isolated was derived from the vertebrate bone marrow, which when transplanted became a therapeutic intervention for many hematological, immune, and metabolic genetic disorders. The study of these cells in vertebrates has enlightened the study of other tissue stem cells. While a large amount of transcriptional profile data is available on these cells, the role of these genetic networks in their function remains unknown. We utilize the lymph gland, the hematopoietic organ in the genetic model organism Drosophila melanogaster, as a framework for understanding the biology of somatic stem cell function. Our studies have identified a hematopoietic stem cell niche within the lymph gland and demonstrate the utility of this system, as it recapitulates many of the developmental principles present in the vertebrate bone marrow. Our goal is to characterize the genetic determinants of cell differentiation in a population of third instar larva lymph gland stem cells. Our first specific aim is to define the roles of niche signals required for the maintenance of hematopoietic precursors in the Drosophila lymph gland. We have identified signaling pathways involved in the establishment and maintenance of the niche. Through the use of molecular genetic approaches we will dissect those signals that regulate the differentiation and self-renewal capabilities of hematopoietic precursors. Our second specific aim is to determine the cell fate potential of hematopoietic stem cells in the Drosophila lymph gland. We have developed transplantation techniques to characterize the developmental potential of whole lymph glands and dissociated hematopoietic stem cells. An unbiased genetic screen is proposed targeted at identifying novel genetic determinants required for the generation of hematopoietic stem cells. Career development activities include mentoring and coursework in genetics and developmental biology. Long-term career goals include an academic position in which I can pursue basic science research on developmental principles in stem cell biology and regeneration, diagnosis and treatment of patients with genetic syndromes, and teaching of medical and graduate students. Our expectation is that a better understanding of the mechanisms that regulate the development and maintenance of hematopoietic stem cells in Drosophila will provide novel mechanisms and therapeutic pathways to be explored in human disease, such as leukemia.
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|Sinenko, Sergey A; Mandal, Lolitika; Martinez-Agosto, Julian A et al. (2009) Dual role of wingless signaling in stem-like hematopoietic precursor maintenance in Drosophila. Dev Cell 16:756-63|
|Mandal, Lolitika; Martinez-Agosto, Julian A; Evans, Cory J et al. (2007) A Hedgehog- and Antennapedia-dependent niche maintains Drosophila haematopoietic precursors. Nature 446:320-4|
|Martinez-Agosto, Julian A; Mikkola, Hanna K A; Hartenstein, Volker et al. (2007) The hematopoietic stem cell and its niche: a comparative view. Genes Dev 21:3044-60|