Lab Research Focus
The principle focus of my research is to understand the molecular basis for self-renewal and lineage commitment of murine hematopoietic stem cells. Hematopoietic stem cells represent a rare population of adult bone marrow cells which can regenerate themselves (self-renew) as well as differentiate into the wide variety of cell types which comprise the hematopoietic system. The self-renewing activity is sufficient to extent well beyond many normal mouse lifespans based on serial bone marrow transplantation experiments. At present, nothing is known about how self-renewal and differentiation are regulated at the molecular level.
We are currently addressing these issues by studying the function of various transcription factors which, in a loss-of-function context, have a direct affect on stem cell function. Such factors include Ikaros, PU.1, AML-1, and EBF. The experimental approaches which are being used include the generation of transgenic and ES cell knockout animals, retroviral transduction of stem cells, bone marrow reconstitution assays, single-cell RT-PCR, and expression screening. We are also working out a single cell transcription assay in order to clone genes which are key regulators of important genes in stem cells. A recently made stem-cell-specific cDNA library should greatly facilitate these studies.
Our studies also have direct application in the areas of gene therapy, bone marrow transplantation, and stem cell leukemias. With respect to gene therapy, we will be attempting to design retroviral constructs which buffer reporter genes from the transcriptional inactivation which occurs following transduction of stem cells. These studies will not only allow one to do genetic analyses in stem cells using retroviruses but will also be important for establishing mouse models for human gene therapy of hematopoietic disorders.
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