Post-transcriptional Control of Adaptive Tissue Growth

适应性组织生长的转录后控制

• 批准号: 9365361
• 负责人: Nicholas Sokol
• 金额: $ 34.05万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9365361
• 关键词: Address; Adult; Affect; Aging; Alpha Cell; Animal Model; Animals; Area; Behavior; Binding; Biochemical; Biochemical Genetics; Biological; Candidate Disease Gene; Cell Count; Cell division; Complex; Congenital Disorders; Cues; Development; Drosophila genus; Equilibrium; FMR1; Fragile X Syndrome; Genetic; Genetic Epistasis; Genetic Transcription; Genetic Translation; Goals; Grant; Growth; Human; Insulin Receptor; Intervention; Intestines; Investigation; Joints; Lead; Lobular Neoplasia; Malignant Neoplasms; Measures; Medical; Messenger RNA; Methods; Microscopy; Midgut; Modeling; Molecular; Natural regeneration; Nutrient; Pathway interactions; Pattern; Play; Post-Transcriptional Regulation; Process; Proteins; Proteomics; RNA-Binding Proteins; Reporting; Ribonucleoproteins; Role; Starvation; Stem cells; System; Testing; Tissues; Translating; Translations; Vertebrates; Work; adult stem cell; base; cancer therapy; cofactor; cohort; detection of nutrient; experimental study; fly; food consumption; genetic approach; human disease; improved; insight; intestinal epithelium; messenger ribonucleoprotein; mutant; novel; regenerative; regenerative therapy; response; screening; self-renewal; stem cell biology; stem cell division; stem cell population; tool; transcriptomics

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.

项目总结 在这里，我们试图了解成体干细胞内mRNAs的翻译控制是如何控制其 对称分割的能力。这一研究领域很重要，因为这种对称更新是一种 干细胞的基本但鲜为人知的行为，它负责组织生长、重塑 以及包括人类在内的动物的再生。针对这一缺陷，我们发现RNA结合 LIN-28蛋白在果蝇模型的成体肠道干细胞中特异表达 在肠道的生长过程中，这一干细胞群的扩张是必需的 上皮细胞对食物消耗的反应。因为脊椎动物LIN-28也已知能促进 再生，这笔赠款的目标是利用遗传上易驯服的果蝇的独特优势 严格描述保守的机械性活动、相关底物和所需辅因子的模型 LIN-28通常用来促进干细胞的对称更新。我们计划实现这一目标 我们的目标是将我们的实验集中在一个特定的假设上，该假设基于我们对LIN-28的功能分析 在ISCs以及大规模的蛋白质组和转录组分析中，我们发现了 LIN-28在ISCs中的结合伙伴和信使核糖核酸靶标。我们的假设是，一种特定的干细胞 核糖核蛋白(RNP)复合体，包括LIN-28，在营养胁迫过程中促进靶mRNAs的翻译。 在缺乏营养的条件下，使干细胞能够在有营养的情况下对称分裂。至 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 适应性生长受LIN-28和另一种称为FMR1的RNA结合蛋白之间的比率控制 ISCS；2)确定LIN28和FMR1在适应性组织大小调整过程中如何调节mRNA靶标；3) 研究LIN28和FMR1是否通过从更大的mRNP复合体中排除彼此来发挥作用。我们 预计这些拟议的研究将描绘出一条新的、保守的途径，控制对称的自我 干细胞对环境信号的响应而更新。触发这一途径的医学干预 可用于促进再生过程，因此在治疗中具有广泛的适用性 与衰老和先天性疾病有关的疾病。