Hematopoiesis and vasculogenesis are interdependent developmental processes involving the formation of blood cells and vascular structures. Although numerous signaling transducers and transcriptional regulators have been implicated in hemato-vascular development, little is known about the early mechanisms that underlie induction and patterning of the mesodermal cells that will be specified along hematopoietic and vascular endothelial lineages. In this project I will examine the potential role of the murine Mix (mMix) homeoprotein in mesoderm induction and early hemato-vascular development. In the early embryo, expression of the mMix gene partially overlaps that of another mesodermal gene, Brachyury (T), in the primitive streak and nascent mesoderm. In ES cell-derived embryoid bodies, mMix and T are coexpressed in a population of mesoderm with hematopoietic and endothelial (hemangioblastic) potential, prior to the appearance of differentiated hematopoietic and endothelial cells. Targeted disruption of the mMix gene results in a collection of defects that include abnormalites in allantoic (umbilical vasculature) and heart morphogenesis. Because mMix is a DNA-binding transcription factor, I hypothesize that mMix may regulate genes required for the induction and/or patterning of some populations of hemato-vasculogenic mesoderm. A combination of genetic, cell biological, biochemical and bioinformatics approaches will be employed to address the following three aims: (1) To examine the ability of Mix to regulate induction and/or patterning of hematopoietic and vascular mesoderm in differentiating ES cells; (2) To characterize the transcriptional properties of the mouse Mix protein; and (3) To identify potential target genes of mMix using functional genomics. These studies will uncover early regulatory events in hematopoietic and vascular development and will, therefore provide novel insights into the formation, self-renewal, and differentiation of hematopoietic and endothelial stem/progenitor cells. They may ultimately facilitate the development of new stem/progenitor cell therapies for treatment of hematologic and other malignancies and find important applications in regenerative medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK070752-03
Application #
7223502
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Bishop, Terry Rogers
Project Start
2005-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$124,589
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029