Final Paper Proposal Example

Final Paper Proposal Example - Dissecting the cell...

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Dissecting the cell composition of a stem cell niche based on proliferation history Abstract We are interested in elucidating the molecular mechanisms involved in somatic stem cell self- renewal and fate choice, in normal tissue development and homeostasis. Stem cells hold great promises for future therapies of numerous deadly diseases, yet their basic properties are not well understood. Progress in the field has been hampered by the difficulty of identifying tissue stem cells in the absence of specific biochemical markers. Increasing evidence suggested that stem cells are infrequently dividing cells, that could be identified in many mouse tissues as DNA label retaining cells (or LRCs). Recently we developed a strategy applicable to many self-regenerating tissues to pulse-label LRCs with the green fluorescent protein (GFP) fused to histone H2B. We have used the mouse skin and the hair follicle as model systems, since the relation between LRCs and skin epithelial stem cells had been investigated in most depth. In our preliminary work we tracked and isolated GFP LRCs and demonstrated that at least a fraction of these cells had a stem cell phenotype. In this proposal we describe in 2 Specific Aims strategies to examine in more detail the relation between LRCs and stem cells. We will: 1) classify LRCs into distinct sub-populations and investigate their stemness; 2) characterize their distinct patterns of gene expression. To accomplish these goals we use in vivo cell tracking and in vitro cell sorting methods combined with a variety of assays which include: hair follicle regeneration and skin wounding; cell culture and skin reconstitution; and microarrays. First, our data will have global relevance for the isolation and characterization of putative stem cells with LRCs properties from many other tissues. Although we focus on the hair follicle, our work will lead the way for similar approaches in many systems which lack the specific means to separate stem cells from other cells of their tissue of residence. Finally, our work will provide some of the basic knowledge which will be necessary for more efficient manipulation of skin stem cells for clinical applications such as cell transplantation on burn victims. 1
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Introduction Tissue stem cells are cells that self-renew and differentiate during the entire life of the animal. A long-standing hypothesis in the stem cell field stated that tissue stem cells were infrequently dividing cells, and that this mechanism has been developed to protect stem cells from accumulating multiple mutations during repeated replication (Watt and Hogan 2000; Fuchs et al. 2004). Although some experimental evidence supported this hypothesis, the direct link between infrequently dividing cells and stem cells has not been clearly established. Skin is a self-regenerating tissue, which contains its own pool of specialized tissue stem cells. Mammalian skin consists of two tissue layers: epidermis and dermis. Epidermis is largely composed of keratinocytes, which make up the
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Final Paper Proposal Example - Dissecting the cell...

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