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.

项目概要/摘要 本提案中描述的研究旨在回答与 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 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 整个有机体的发育进程？ (3)器官如何感知损伤或损伤，然后 激活一个程序来再生缺失的组织？ (4) 为什么再生能力会减弱 有机体成熟了，有没有办法提高再生能力？许多人类疾病，例如出生 缺陷和癌症的特征是生长调节异常。了解机制 因此，调节生长的药物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 果蝇果蝇的遗传方法。通过筛选使细胞生长过度的突变 与它们的野生型邻居相比，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 Hippo 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，我们创建了一个系统，其中组织 成虫盘可能因温度变化而被烧蚀。我们已经使用这个系统来表明许多途径 随着有机体成熟，对于再生生长重要的物质被激活的效率降低。以Wnt为例 基因表达，这是由于损伤反应增强子的局部表观遗传沉默所致。 未来几年的目标是继续表征调节组织范围的突变 生长，并使用以下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核定位的变化，因为组织 接近其最终尺寸。分泌蛋白在传达个体器官生长状态方面的作用 将研究神经内分泌系统，从而调节发育时间。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组织损伤引起的染色质状态变化。我们将使用一个 新颖的系统“双重控制”，用于筛选可改善成熟组织再生的基因操作。