Post-transcriptional Control of Adaptive Tissue Growth

项目摘要 在这里，我们试图了解成人干细胞内mRNA的翻译控制如何控制其功能。 对称分割的能力。这一研究领域是重要的，因为这种对称更新是一种 干细胞的基本但知之甚少的行为，负责组织生长，重塑 以及包括人类在内的动物的再生。为了解决这一缺陷，我们发现RNA结合 蛋白质LIN-28在果蝇模型的成体肠干细胞（ISC）中特异性表达 在肠道生长过程中，干细胞群的扩增是必需的。 上皮细胞对食物消耗的反应。由于脊椎动物LIN-28也已知促进 再生，这项赠款的目标是利用遗传上易于驾驭的果蝇的独特优势， 严格描述保守的机械活性，相关底物和所需辅因子的模型 LIN-28通常用于促进干细胞的对称更新。我们建议做到这一点 通过将我们的实验集中在基于LIN-28功能分析的特定假设上， 在ISCs以及大规模的蛋白质组学和转录组学分析中，我们进行了鉴定， ISC中的LIN-28结合配偶体和mRNA靶标。我们的假设是一种干细胞特异性 核糖核蛋白（RNP）复合物，包括LIN-28，在营养过程中促进靶mRNA的翻译 为了平衡干细胞，当营养物质可用时，干细胞会对称地分裂。到 为了实现我们的目标，我们提出了以下三个重叠的调查领域：1）测试是否 适应性生长是由LIN-28和另一种称为FMR 1的RNA结合蛋白之间的比例控制的。 ISC; 2）确定LIN 28和FMR 1在适应性组织增殖期间如何调节mRNA靶标; 3） 研究LIN 28和FMR 1是否通过从更大的mRNP复合物中排除彼此而发挥作用。我们 我希望这些研究能描绘出一个新的、保守的控制对称性自我调节的途径， 更新干细胞以响应环境线索。触发这一途径的医疗干预 可用于促进再生过程，因此在治疗中具有广泛的适用性。 与衰老有关的疾病和先天性疾病。

PROJECT SUMMARY Here we seek to understand how translational control of mRNAs within adult stem cells controls their ability to divide symmetrically. This area of study is significant because such symmetric renewal is a fundamental but poorly understood behavior of stem cells that is responsible for tissue growth, remodeling and regeneration in animals including humans. Addressing this deficit, we have found that the RNA-binding protein LIN-28 is specifically expressed in adult intestinal stem cells (ISCs) of the Drosophila model organism and is required for the expansion of this stem cell population during growth of the intestinal epithelium in response to food consumption. Since vertebrate LIN-28 is also known to promote regeneration, the goal of this grant is to use the unique advantages of the genetically tractable Drosophila model to rigorously delineate the conserved mechanistic activity, relevant substrates, and required cofactors that LIN-28 normally uses to promote the symmetric renewal of stem cells. We propose to accomplish this goal by focusing our experiments on a specific hypothesis that is based on our functional analysis of LIN-28 in ISCs as well as large scale proteomic and transcriptomic analyses we conducted that identified putative LIN-28 binding partners and mRNA targets in ISCs. Our hypothesis is that a stem cell specific ribonucleoprotein (RNP) complex, including LIN-28, boosts translation of target mRNAs during nutrient- deprived conditions in order to poise stem cells to divide symmetrically when nutrients become available. To accomplish our goal, we propose the following three overlapping areas of investigation: 1) Test whether adaptive growth is controlled by the ratio between LIN-28 and a second RNA-binding protein called FMR1 in ISCs; 2) Determine how LIN28 and FMR1 regulate mRNA targets during adaptive tissue resizing; 3) Investigate whether LIN28 and FMR1 function by excluding one another from a larger mRNP complex. We expect that these proposed studies will delineate a novel, conserved pathway that controls symmetric self- renewal of stem cells in response to environmental cues. Medical interventions that trigger this pathway could be used to promote the regenerative process and therefore would have wide applicability in treating aging-related and congenital disorders.