CELLULAR AND MOLECULAR STUDIES OF THE STEM CELL NICHE

描述（由申请人提供）：果蝇干细胞龛为理解哺乳动物干细胞行为提供了有用的模型。在确定控制组成性活性小生境（如生殖系和肠道）的原则方面取得了很大进展。然而，静止的干细胞小生境，可以再生的组织，以响应损伤是不太好理解。我们的研究最近导致了一种新的胃干细胞（GSSC）在成年果蝇胃的鉴定。GSSC表现出许多独特的行为。对于这一建议，重要的是，胃干细胞通常是静止的，但被快速诱导 以再生整个胃上皮以响应组织破坏性损伤。我们的初步数据表明，GSSC是由保守的信号通路，这已经牵连在哺乳动物和无脊椎动物干细胞壁龛，包括在胃肠道中发现的控制。这些观察结果提出了一个中心假设，即胃中的上皮再生是通过一个区域特异性的小生境程序实现的，该程序使GSSC适应于独特的胃生理学。在目的1中，我们提出测试胃干细胞在静止小生境中维持的机制。在目标2中，我们提出了表征调节胃干细胞静止的信号。在目标3中，我们提出解决三能胃谱系中细胞命运特化的基础。这些问题目前很难回答。 在哺乳动物中，由于胃的主要胃干细胞尚未确定。因此，我们建议使用果蝇作为一个模型来剖析控制静止胃干细胞龛的机制。

DESCRIPTION (provided by applicant): Drosophila stem cell niches provide useful models for understanding mammalian stem cell behavior. Great progress has been made in defining principles that control constitutively active niches such as the germ line and intestine. However, the quiescent stem cell niche that can regenerate a tissue in response to injury is less well understood. Our studies have recently led to the identification of a novel gastric stem cell (GSSC) in the adult Drosophila stomach. GSSCs exhibit a number of unique behaviors. Significantly for this proposal, gastric stem cells are normally quiescent, but are rapidly induced to regenerate the entire gastric epithelium in response to tissue damaging injury. Our preliminary data indicate that GSSCs are controlled by conserved signaling pathways, which have been implicated in mammalian and invertebrate stem cell niches, including those found in the gastrointestinal tract. These observations raise the central hypothesis that epithelial regeneration in the stomach is achieved through a region-specific niche program, which adapts the GSSC to a unique stomach physiology. In Aim 1 we propose to test the mechanism of gastric stem cell maintenance in a quiescent niche. In Aim 2 we propose to characterize the signals that regulate gastric stem cell quiescence. In Aim 3 we propose to address the basis of cell fate specification in a tri-potent gastric lineage. These questions are currently difficult to address in mammals, as the principle gastric stem cells of the stomach have not yet been identified. Thus, we propose to use Drosophila as a model to dissect the mechanisms controlling a quiescent gastric stem cell niche.