Dr. Diane Krause

The overall goals of my research are to characterize bone marrow derived (BM) stem and progenitor cells, and to define the mechanisms that regulate the self-renewal and differentiation of these cells with the hopes that the findings can be translated to the development of improved therapeutic strategies. Specifically, my laboratory is pursuing three projects. The first is based on our very exciting discovery that BM derived cells (BMDC) are capable of differentiating into non-hematopoietic cells throughout the body. Specifically, in our early work, we showed that, in both mice and humans, BMDC could differentiate into hepatocytes. In subsequent work, we showed that a single BMDC could differentiate not only into all types of blood cells, but also into mature epithelial cells of the lung, liver, GI tract and skin. These findings are incredibly exciting as they suggest that BMDC could be used to treat lung disease.

Although this field is in its infancy, we have started to identify what promotes the development of these BM derived epithelial cells and have demonstrated potential therapeutic benefit of BM derived cells becoming pneumocytes in mice that model human lung diseases. We have published that retrovirally transduced BM cells continue to express the retroviral transgene even after they differentiate into mature pneumocytes suggesting that gene therapy could potentially be administered to the lung via transplantation of modified BM cells. We have shown that BM transplantation can partially restore CFTR expression and functional activity in the GI tract of mice with cystic fibrosis, and we are actively studying restoration of surfactant protein expression in the lung as well.

These findings have played an important role in opening a new field of research - that of adult stem cell plasticity, and we are optimistic that researchers in this new field will discover creative ways of harnessing the ability of these cells. The mechanisms by which the BM to epithelial cell transition occurs are still under study. We are addressing the controversies in the field of BM cell plasticity regarding whether this occurs due to direct reprogramming of the gene expression pattern of the BM cells or due to cell-cell fusion with subsequent reprogramming of the marrow cell nucleus within the heterokaryon. We and others have performed experiments specifically designed to address whether cell-cell fusion is necessary for the differentiation of marrow derived cells into mature epithelial cells, and our data strongly suggest that, at least in the conditions that we have tested, this transition in cell phenotype can occur without fusion. In some situations, however, other researchers have shown that fusion is the underlying mechanism. Regardless of the mechanism, however, this work may have very exciting clinical applications.

The second major focus in my lab is to define the molecular mechanism(s) that regulate gene expression during developmental and adult hematopoiesis. We have used the CD34 gene as a model system to study the transcriptional regulation of early hematopoiesis because CD34 is expressed in hematopoietic stem cells (HSC), and is downregulated during differentiation. We have published 4 papers on the transcriptional regulation of CD34. More recently, our studies have been focused on the transcriptional co-factors RBM15 and MKL. Acute Megakaryoblastic Leukemia (AMKL) usually presents with one of two genotypic abnormalities; either Down Syndrome (DS, trisomy 21) accompanied by partial loss of function GATA-1 mutations, or non-DS AMKL associated with the translocation t(1;22). Work in the Krause laboratory is focused on the function of the fusion protein, RBM15-MKL that is encoded by translocation t(1;22). In order to elucidate the role of the RBM15-MKL fusion protein in AMKL, we must understand the normal functions of the transcriptional co-factors RBM15 (chromosome 1) and MKL (chromosome 22). We found that Rbm15 and MklI are differentially expressed during hematopoietic differentiation into mature megakaryocytes. In ongoing work, we are studying the effects of RBM15 and MKL on myeloid and megakaryocytic differentiation, as well as the molecular mechanisms of these effects.

The third focus in my laboratory is the development and use of xenogeneic BM transplantation models to optimize human platelet engraftment.

I wish to be contacted by interested post-doctoral candidates as a potential research mentor/advisor.