Tel:	617-919-2015
	Fax:	617-730-0222
	E-Mail:	george.daley@childrens.harvard.edu
	Location:	Children's Hospital 300 Longwood Ave. Boston, MA 02115
	Homepage:	http://daley.med.harvard.edu/

The laboratory focuses on stem cell biology, with an emphasis on hematopoietic differentiation from human and mouse embryonic stem (ES) cells, epigenetic reprogramming, germ cell development, and study of the BCR-ABL oncoprotein of chronic myeloid leukemia (CML), the classic malignancy of hematopoietic stem cells (HSCs). Our goals are described briefly below:

Directed differentiation of HSCs from ES cells: ES cells are pluripotent, yet mechanisms of directed differentiation and models for functional engraftment in diseased animals remain poorly defined. We study hematopoietic development in mouse embryos and differentiating cultures of human and mouse ES cells in order to define the molecular genetic programs that enable formation of HSCs in experimental and therapeutic models.

Derivation of genetically defined ES cells: We use somatic cell nuclear transfer and parthenogenesis in the mouse to model combined cell and gene therapy of human genetic disorders. We are exploring parthenogenesis, nuclear transfer, and reprogramming with defined genetic elements as strategies for deriving genetically defined human embryonic stem cells.

Germ cell development: We have devised methods for directed differentiation of ES cells into primordial germ cells, and techniques for isolation and functional transplantation of spermatagonial stem cells from testes. Using this integrated system, we are exploring strategies for in vitro maturation of ES-derived germ cell populations into functional gametes.

Target-directed chemotherapy for human CML: We characterize the mechanisms of action and modes of resistance of target-directed chemotherapy for the treatment of CML, and use chemical genetics to probe mechanisms of kinase regulation. Using techniques for molecular monitoring of resistance patterns in patients, we are seeking to define optimal combination chemotherapy regimens in human trials.

References:

Geijsen, N., Horoschak, M., Kim, K., Gribnau, J., Eggan, K., and GQ Daley, “Derivation of embryonic germ cells and male gametes from embryonic stem cells.” Nature 2004, 427: 148-154.

Azam M, Nardi V, Shakespeare WC, Latek RR, Bohacek RS, Veach DR, Bornmann, W, Clarkson B, Sawyer TK, Daley GQ. “Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in imatinib resistance” Proceedings of the National Academy of Sciences (USA) 2006 103: 9244-9249.

Kim K, Lerou P, Yabuuchi A, Lengerke C, Ng K, West J, Kirby A, Daly M, Daley GQ. “Histocompatible parthenogenetic murine embryonic stem cells.” Science 2007 Jan 26;315(5811):482-6.

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