Polyploidy after tissue injury: a Drosophila model

组织损伤后的多倍体：果蝇模型

• 批准号: 10442828
• 负责人: Donald T. Fox
• 金额: $ 31.97万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442828
• 关键词: Address; Area; Biology; Bladder; Cardiovascular Diseases; Cell Cycle; Cell Cycle Regulation; Cell Size; Cell division; Cells; Cornea; Cues; DNA Damage; Data; Deformity; Drosophila genus; Epithelial; Epithelial Cells; Esophagus; Evolution; Family; Funding; Gene Expression; Genetic; Genetic Transcription; Genome; Grant; Hindgut; Hybrid Cells; Hybrids; Hyperplasia; Injury; Invaded; Kidney; Knowledge; Laboratories; Large Intestine; Lead; Malignant Neoplasms; Mediating; Midgut; Mitosis; Mitotic; Modeling; Molecular; Multiple Trauma; Natural regeneration; Organ; Organ Model; Pathway interactions; Play; Ploidies; Polyploid Cells; Polyploidy; Population; Positioning Attribute; Prevention; Process; Property; Pylorus; Regulation; Reporting; Role; S phase; Severities; Signal Transduction; Small Intestines; Steroids; Stomach; System; Tissues; Tumor Cell Invasion; Tumor Stem Cells; Work; analog; base; cell injury; cytokine; genetic approach; hormonal signals; hormone regulation; injured; injury and repair; innovation; lead candidate; member; novel; organ regeneration; organ repair; prevent; programs; repaired; response; response to injury; severe injury; stem cells; steroid hormone; tissue injury; tissue regeneration; tissue repair; tissue-repair responses; transcription factor; transcriptome sequencing; transcriptomics; tumor; tumorigenesis; whole genome

Metazoan tissues are diverse in organization and function. This necessitates diverse mechanisms to repair these tissues upon injury. We pioneered study of the Drosophila hindgut (large intestine) to reveal new tissue injury regulation. Using this model, we identified an injury response whereby tissue mass is restored by increasing the DNA content (ploidy) and size of cells that survive injury. This increase in ploidy involves a conserved cell cycle with S phases but no cell division, called the endocycle. Our discovery of endocycles and polyploid cells in tissue repair has been followed by similar discoveries in multiple injured mammalian tissues, including the kidney, bladder, and cornea. Additionally, our work revealed specialized polyploid cell regulation at the injured boundary between the hindgut and adjacent midgut (small intestine). At this boundary, we identified “hybrid” cells of dual hindgut and midgut gene expression. Hybrid cells become polyploid upon injury while engaging in extensive cross-talk with stem cells in the adjacent midgut. However, if the hybrid zone is severely injured, polyploidy is suppressed, and the adjacent midgut stem cells form hyperplastic invasive tumors. Similar hybrid zones have now been discovered at mammalian organ boundaries, notably at the stem cell-enriched, cancer-prone stomach/esophagus boundary. This proposal leverages our expertise, new findings, and the genetically amenable Drosophila model to identify regulation and function of polyploidy after tissue injury. The significance of our proposed work is evident in the conservation of the injury response, the conservation of endocycles in injury, and the conservation of the molecules we study, including JAK/STAT signaling, Dichaete/SoxB1, and fizzy-related/cdh1. Our studies are innovative because they show that tissues can regenerate by accurately controlling polyploid genome number, that hormonal signaling and Sox transcription cooperate to control injury-induced polyploidy, and that a regenerating polyploid organ boundary can suppress tumorigenesis. In Aim1, we will uncover how injury severity determines the extent of polyploidy during regeneration. To answer this question, we will identify quantitative parameters of JAK/STAT signaling at different injury strengths and identify specific pathway steps that coordinate injury level with endocycle number. Aim2 will identify the molecular mechanism by which endocycles occur after injury instead of mitosis. To answer this question, we will examine how Dichaete, a member of the conserved Sox transcription factor family, cooperates with hormone signaling to promote a switch from injury-induced mitotic cycles to endocycles. Aim3 will determine the origin and function of polyploid hybrid cells following injury. To answer this question, we will distinguish between stem cell-dependent and stem cell-independent models of organ boundary regeneration. Additionally, this aim will reveal the role of the hybrid zone and polyploidy in repressing stem cell tumor invasion. All three aims capitalize on transcriptomic data and our unique precision injury/genetics system to identify novel molecular players in an evolutionarily conserved tissue repair response.

后生动物组织的组织和功能多种多样。这就需要多种机制来 在受伤时修复这些组织。我们率先研究果蝇后肠（大肠），揭示新的 组织损伤调节。使用这个模型，我们确定了一种损伤反应，通过这种方式恢复组织质量 增加损伤后存活的细胞的 DNA 含量（倍性）和大小。这种倍性的增加涉及 具有S期但没有细胞分裂的保守细胞周期，称为内周期。我们对内循环的发现和 组织修复中的多倍体细胞在多种受伤的哺乳动物组织中也有类似的发现， 包括肾脏、膀胱和角膜。此外，我们的工作揭示了专门的多倍体细胞调控 后肠和相邻中肠（小肠）之间的受伤边界。在这个边界上，我们确定了 后肠和中肠双重基因表达的“混合”细胞。杂交细胞在损伤后变成多倍体，同时 与邻近中肠的干细胞进行广泛的串扰。但如果混合区严重 受伤后，多倍体受到抑制，邻近的中肠干细胞形成增生性侵袭性肿瘤。相似的 现在在哺乳动物器官边界发现了混合区，特别是在富含干细胞的区域， 易患癌症的胃/食道边界。 该提案利用我们的专业知识、新发现和遗传上适合的果蝇模型 确定组织损伤后多倍体的调节和功能。我们提出的工作的重要性是显而易见的 在损伤反应的保护、损伤中内环的保护以及 我们研究的分子，包括 JAK/STAT 信号传导、Dichaete/SoxB1 和 fizzy-lated/cdh1。我们的研究是 创新是因为它们表明组织可以通过精确控制多倍体基因组数量来再生， 激素信号传导和 Sox 转录协同控制损伤诱导的多倍体，并且 再生多倍体器官边界可以抑制肿瘤发生。在目标 1 中，我们将揭示伤害的严重程度 决定再生过程中多倍体的程度。为了回答这个问题，我们将确定定量 不同损伤强度下 JAK/STAT 信号传导的参数，并确定协调的特定途径步骤 损伤程度与内循环数有关。 Aim2 将确定内环发生后的分子机制 损伤而不是有丝分裂。为了回答这个问题，我们将研究保守家族成员 Dichaete 是如何 Sox 转录因子家族，与激素信号传导合作，促进损伤诱导的有丝分裂的转变 循环至内循环。 Aim3 将确定损伤后多倍体杂交细胞的起源和功能。到 回答这个问题，我们将区分干细胞依赖性和干细胞非依赖性模型 器官边界再生。此外，这一目标将揭示杂交区和多倍体在 抑制干细胞肿瘤的侵袭。所有三个目标都利用转录组数据和我们独特的精度 损伤/遗传学系统来识别进化上保守的组织修复反应中的新分子参与者。