CELLULAR AND MOLECULAR STUDIES OF THE STEM CELL NICHE

描述(申请人提供)：果蝇干细胞壁龛为理解哺乳动物干细胞行为提供了有用的模型。在确定控制生殖系和肠道等构成活性生态位的原则方面已经取得了很大进展。然而，能够在损伤后再生组织的静止干细胞生态位却鲜为人知。我们的研究最近在成年果蝇胃中发现了一种新的胃干细胞(GSSC)。GSSC表现出许多独特的行为。值得注意的是，胃干细胞通常是静止的，但很快就会被诱导出来。 以再生整个胃上皮，以应对组织损伤。我们的初步数据表明，GSSCs受保守的信号通路控制，这些信号通路与哺乳动物和无脊椎动物干细胞的生态位有关，包括在胃肠道中发现的干细胞。这些观察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定的利基计划实现的，该计划使GSSC适应独特的胃生理。在目标1中，我们建议在静止的壁龛中测试胃干细胞维持的机制。在目标2中，我们建议描述调节胃干细胞静止的信号。在目标3中，我们建议解决三能胃谱系中细胞命运指定的基础。这些问题目前很难回答 在哺乳动物中的地址，因为胃的主要胃干细胞尚未被鉴定。因此，我们建议使用果蝇作为一个模型来剖析控制静止的胃干细胞生态位的机制。 与公共卫生相关：干细胞具有巨大的潜力，可以影响人类疾病的治疗和治愈。为了在再生医学和基于细胞的治疗中有效地利用干细胞，现在需要建立干细胞在其自然环境中如何调节的准确模型。对果蝇的研究对人类具有巨大的预测力，因为生物守恒的统一原则存在于细胞和分子水平

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. PUBLIC HEALTH RELEVANCE: Stem cells have enormous potential to impact the treatment and cure of human disease. Accurate models of how stem cells are regulated in their native environments are now needed to effectively utilize stem cells in regenerative medicine and cell-based therapies. Studies in Drosophila have great predictive power for humans because of the unifying principles of biological conservation that exist at both the cellular and molecular levels