Genetic Regulation of Developmental and Regenerative Growth

发育和再生生长的遗传调控

• 批准号: 9900021
• 负责人: Iswar K. Hariharan
• 金额: $ 54.75万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900021
• 关键词: Affect; Affinity; Back; Cells; Chromatin; Congenital Abnormality; Development; Disease; Drosophila genus; Drosophila melanogaster; Enhancers; Epigenetic Process; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Growth; Imaging Techniques; Individual; Injury; Malignant Neoplasms; Measures; Methods; Mutation; Natural regeneration; Nuclear; Organ; Organism; Pathway interactions; Proteins; Regulation; Research; Role; Sense Organs; Shapes; System; Temperature; Tissues; Tumor Suppressor Genes; cell growth; genetic approach; genetic manipulation; genome-wide; human disease; imaginal disc; improved; insight; mutation screening; novel; novel therapeutics; programs; quantitative imaging; regenerative

PROJECT SUMMARY/ABSTRACT The research described in this proposal is aimed at answering four fundamental questions that relate to the regulation of growth: (1) How is the growth of many individual cells regulated so that they collectively generate a tissue or organ of a specific shape and size? (2) How does the growth of specific tissues affect the developmental progression of the entire organism? (3) How does an organ sense injury or damage and then activate a program to regenerate missing tissue? (4) Why does the capacity for regeneration diminish as an organism matures and are there ways of improving regenerative capacity? Many human diseases such as birth defects and cancer are characterized by an abnormal regulation of growth. Understanding the mechanisms that regulate growth will therefore point to novel therapeutic strategies for these conditions. Our studies will also suggest ways for improving regeneration following tissue damage. To obtain a better understanding of both growth during development and regenerative growth, we use a genetic approach in the fruit fly Drosophila melanogaster. By screening for mutations that make cells outgrow their wild-type neighbors, we have identified many genes whose normal function is to restrict tissue growth including components of the Hippo pathway. The ortholgs of some of these genes have been shown to be tumor-suppressor genes. To study regenerative growth, we have generated a system where tissue in the imaginal disc can be ablated by a temperature shift. We have used this system to show that many pathways important for regenerative growth are activated less efficiently as the organism matures. In the case of Wnt gene expression, this is due to localized epigenetic silencing of a damage responsive enhancer. The goal in the coming years is to continue the characterization of mutations that regulate the extent of tissue growth, and to identify additional genes that regulate cell growth, cell competition and cell affinity using the CoinFLP method. To assess the activity of growth regulating pathways in individual cells, quantitative imaging techniques will be used to measure changes in nuclear localization of transcriptional regulators as the tissue approaches its final size. The role of secreted proteins that communicate the growth status of individual organs to the neurodendocrine system, so as to regulate the timing of development, will be studied. To characterize changes in regenerative capacity, we will study multiple damage-responsive enhancers in detail as well as use genome-wide approaches to characterize changes in chromatin states elicited by tissue damage. We will use a novel system, Dual Control, to screen for genetic manipulations that improve regeneration in mature tissues.

项目总结/摘要 本建议中所述的研究旨在回答与以下方面有关的四个基本问题： 生长调节：（1）如何调节许多单个细胞的生长，使它们共同产生 一种特定形状和大小的组织或器官(2)特定组织的生长如何影响 整个生物体的发育过程(3)一个器官是如何感觉到受伤或损伤， 启动程序来再生缺失的组织(4)为什么再生能力会随着时间的推移而减弱？ 生物体成熟，有没有提高再生能力的方法？许多人类疾病如生育 缺陷和癌症的特征在于生长的异常调节。了解机制 因此，调节生长的基因将为这些疾病提供新的治疗策略。我们的研究将 还提出了改善组织损伤后再生的方法。 为了更好地理解发育过程中的生长和再生生长，我们使用 遗传学方法在果蝇Drosophila melanogaster。通过筛选突变， 我们已经鉴定出许多正常功能是限制组织生长的基因， 包括河马途径的组成部分。其中一些基因的直系同源物已被证明是 肿瘤抑制基因为了研究再生生长，我们已经建立了一个系统， 通过温度变化可以切除胚盘。我们用这个系统证明了许多途径 对再生生长很重要的蛋白质随着有机体的成熟而被激活的效率降低。在Wnt的情况下， 基因表达，这是由于损伤应答增强子的局部表观遗传沉默。 未来几年的目标是继续表征调节组织范围的突变， 生长，并使用该方法鉴定调节细胞生长、细胞竞争和细胞亲和力的其他基因。 CoinFLP方法。为了评估单个细胞中生长调节途径的活性，定量成像 技术将用于测量转录调节因子的核定位的变化， 接近其最终尺寸。分泌蛋白的作用，沟通个别器官的生长状态 神经内分泌系统，以调节发育的时间，将进行研究。表征 再生能力的变化，我们将详细研究多种损伤响应增强剂，以及使用 全基因组方法来表征由组织损伤引起的染色质状态的变化。我们将使用一个 新的系统，双重控制，以筛选基因操作，提高再生成熟组织。