Genetic Regulation of Developmental and Regenerative Growth

发育和再生生长的遗传调控

• 批准号: 10406520
• 负责人: Iswar K. Hariharan
• 金额: $ 61.22万
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406520
• 关键词: Adult; Anterior; Atlases; Back; Cell Proliferation; Cell Shape; Cell Surface Proteins; Cell Survival; Cells; Congenital Abnormality; Development; Disease; Distant; Drosophila genus; Experimental Genetics; Genes; Genetic; Genetic Screening; Goals; Growth; Heterogeneity; Individual; Ion Channel; Ligands; Malignant Neoplasms; Membrane Potentials; Natural regeneration; Organ; Pattern; Piezo ion channels; Property; Regulation; Research; Role; Shapes; Structure; Wing; Work; blastema; gene function; gene regulatory network; imaginal disc; improved; in vivo; insight; planar cell polarity; receptor; regenerative growth; smoothened signaling pathway; tool; transcriptomics

PROJECT SUMMARY/ABSTRACT The overall goal of our research is to understand the mechanisms that regulate growth: at the level of the individual cell, at the level of organs and at an organismal level. In order to study the regulation of growth, we have studied the imaginal discs of Drosophila, the larval precursors of adult structures such as the wing. Until recently, an important limitation to our work was that we had few tools to study the cellular heterogeneity that is a key feature of growth regulation in vivo. Single-cell transcriptomics allows us to characterize small subsets of cells that have a major impact on growth regulation. By combining this approach with experimental genetics, we can now study a key aspects of growth regulation that involves heterotypic interactions between small subsets of cells. We aim to obtain a better understanding of the genetic regulation of regenerative growth. We have identified a gene regulatory network that is entirely dispensable for normal development but is essential for regenerative growth. Additional genes identified from our single-cell studies point to genes that are specifically expressed in different portions of the regeneration blastema and which likely regulate different aspects of regeneration including proliferation, cell shape and cell-fate plasticity. We will characterize the function of these genes. We have also found that damage and regeneration of one portion of the disc can impact the development of the remainder of the disc and also distant organs. Another goal is to elucidate the mechanistic basis of these long- range phenomena. We will examine the role of ion channels in regulating Hedgehog signaling and the growth and patterning of the of the wing disc. We will determine why cells with a more depolarized membrane potential survive preferentially in the anterior compartment of the wing disc. We will also study the properties of the mechanosensitive channel Piezo in growth regulation. Finally, by combining our single cell atlas of the wing disc with a genetic screen, we have identified many genes encoding poorly-characterized cell-surface proteins and ligand-receptor pairs that likely function during development to regulate cell survival, cell proliferation and planar cell polarity. We will study these genes.

项目概要/摘要 我们研究的总体目标是了解调节生长的机制：在 单个细胞、器官水平和有机体水平。为了研究生长的调控，我们 研究了果蝇的成虫盘，这是成虫结构（如翅膀）的幼虫前身。 直到最近，我们工作的一个重要限制是我们几乎没有工具来研究细胞异质性 这是体内生长调节的一个关键特征。单细胞转录组学使我们能够表征小细胞 对生长调节有重大影响的细胞亚群。通过将这种方法与实验相结合 遗传学，我们现在可以研究生长调节的一个关键方面，其中涉及之间的异型相互作用 小的细胞亚群。 我们的目标是更好地了解再生生长的遗传调控。我们已经确定了一个 基因调控网络对于正常发育完全可有可无，但对于再生至关重要 生长。从我们的单细胞研究中鉴定出的其他基因指出了在 再生胚基的不同部分，可能调节再生的不同方面 包括增殖、细胞形状和细胞命运可塑性。我们将描述这些基因的功能。我们 我们还发现椎间盘某一部分的损坏和再生会影响椎间盘的发育 椎间盘的其余部分以及远处的器官。另一个目标是阐明这些长期的机制基础 范围现象。 我们将研究离子通道在调节 Hedgehog 信号传导以及细胞生长和模式中的作用。 翼盘。我们将确定为什么膜电位去极化程度更高的细胞能够存活 优先在翼盘的前室中。我们还将研究其属性 生长调节中的机械敏感通道压电。 最后，通过将我们的翼盘单细胞图谱与遗传筛选相结合，我们已经识别出许多 编码特征较差的细胞表面蛋白和配体-受体对的基因，这些蛋白和配体-受体对可能在 发育以调节细胞存活、细胞增殖和平面细胞极性。我们将研究这些基因。