Stem Cell and Developmental Biology Research Overview - Molecular Pathology

Research Overview - Stem Cell and Developmental Biology

The Stem Cell and Developmental Biology faculty take a diverse approach to developing technology for regenerative medicine. Among the major emphases are the identification and characterization of stem cell populations in adult tissues and organs, research into naturally occurring molecules that promote stem cell renewal, survival and differentiation, and the use of automated robotics to screen for small molecules, proteins and genes that can be used to modulate stem cell behavior. The range of cells under study include embryonic stem cells (ESCs), including human ESCs, and adult stem cells, as well as tumor stem cells, which are thought to be responsible for the malignant and proliferative potential of numerous cancers.

Dr. Martin Haas characterizes human stem cells derived from the amniotic fluid of pregnant women. The cells are grown to large numbers in culture, express markers of human ES cells plus a set of markers of human mesenchymal stem cells and they differentiate into a variety of directions. They also work on human cancer stem cells (CSC) from critical human cancer sources. A study of CSCs in specific human cancers, their characteristics and a correlation between the presence of CSCs in surgical samples and the outcomes of the specific cases is being pursued. Dr. Robert Oshima studies the control of gene expression involved in epithelial tumorigenesis and progression. His lab generates transgenic mouse models of cancer for the study of oncogenes and tumor suppressor gene regulation of cancer progression, metastasis and maintenance of cancer stem cell populations. Of particular interest are ets transcription factors, in particular their involvement in the Neuregulin/ErbB2 pathway important for breast cancer. Dr. Bing Ren is using a genome-wide approach to characterize the transcriptional regulatory networks that control genome expression in human cells, with a particular focus on the pathways that control proliferation and survival of embryonic stem cells and cancer cells. Dr. Xiang-dong Fu studies mRNA splicing and is characterizing how cell-type specific slicing is regulated by kinase signaling cascades during development and in cancer cells. His lab also is developing bioinformatics resources for mRNA splicing research and microarray design.

In the hematopoietic arena, Dr. Bruce Torbett studies transcription factor control of hematopoietic cell differentiation through transgenic mouse technology and has discovered an ets transcription factor, PU.1, that controls differentiation of B and dendritic cells, monocytes/macrophages, and mature neutrophils. Dr. Mark Kamps research involves understanding the role of the Hox, Pbx, and Meis families of homeodomain transcription factors in controling the balance between hematopoietic stem cell self-renewal and differentiation. These homeodomain proteins are active in early progenitors, and their functions are activated in leukemia, a cancer in which stem cells proliferate without differentiating. Dr. Steffan Ho studies the complex regulation of T-cell differentiation by the transcription factor NFAT and also is taking a chemical genetics approach to study the mechanisms that localize proteins to compartments within cells. Dr. Christopher Glass' lab is defining the molecular mechanisms by which sequence-specific transcription factors control the development and function of macrophages, which differentiate from myeloid stem cells in the marrow.

For cardiology, Dr. Rolf Bodmer elucidates gene networks, cell lineages and molecular mechanisms that specify and modulate the development, function and aging of the Drosophila heart as a model. Use of the Drosophila heart as a bioassay to identify polygenic traits and genetic interactions that contribute to congenital and 'sporadic' heart disease. Dr. Sylvia Evans is exploring is exploring cardiac lineage determination, and congenital heart disease, utilizing the mouse as a model system. The Evans lab is studying two potential progenitor/stem cell populations, one which gives rise to cardiomyocytes, and another which gives rise to cells of the coronary vasculature and fibroblasts in the heart. Dr. Mark Mercola discovers molecules and genes for cardiomyocyte regeneration from mouse and human embryonic stem cells (ESC). Part of this effort uses frog, chick and mouse embryos to characterize genetic pathways that induce and pattern the heart. A major part of the lab is involved in a collaborative effort involving chemists and instrumentation experts to perform high throughput screens for gene, protein and small molecule inducers of ESC cardiogenesis. Similarly, for diabetes, Dr. Fred Levine is interested in cell replacement therapy. To that end, his lab has been developing human beta-cell lines. More recently, they have begun studying adult human pancreatic endocrine stem cells and developing high throughput drug screens for chemical inducers of beta-cell differentiation. For skeletal muscle, Dr. Eva Engvall uses stem cells and growth and differentiation factors to protect and renew skeletal muscle in degenerative diseases and aging.

Neurobiology is a major emphasis of a number of laboratories in the Program. Dr. Fred Gage is interested in the molecular and cellular mechanisms of neural stem cell fate determination and subsequent functional integration. Dr. Stuart Lipton was the first clone and characterize the family of MEF2 transcription factors in the brain, where MEF2 is neurogenic and anti-apoptotic. Studies of MEF2 function in vitro and in vivo, including transplantation of MEF2-engineered cells, are in progress along with testing various other neuroprotective agents and pathways. Dr. Geoff Rosenfeld investigates the molecular mechanisms by which several classes of transcription factors, including nuclear receptors, POU domain and homeodomain factors, alter gene expression and orchestrate organ development of the mammalian neuroendocrine and neural systems. His lab has uncovered novel proteins and complex transcriptional regulation that determine the coordinated appearance of specific cell phenotypes in the pituitary gland. Dr. Evan Snyder is interested in differentiation and integration of neural stem cells and their application in models of degenerative disease and oncology. His lab also studies the maintenance of pluripotency and the induction of neural differentiation of human ESCs.

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