Regulation of cell growth and proliferation

细胞生长和增殖的调节

• 批准号: 10395545
• 负责人: Bruce Alexander Edgar
• 金额: $ 75.26万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10395545
• 关键词: ATAC-seq; Address; Animals; Autoimmune Diseases; Back; Binding; Biogenesis; CCNE2 gene; CDC45L gene; Catalogs; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cell division; Cells; Cellular biology; Complex; Coupled; DNA biosynthesis; Degenerative Disorder; Developmental Biology; Diagnosis; Disease; Drosophila genus; E2F transcription factors; Enterocytes; Epidermal Growth Factor Receptor; Epithelial; FRAP1 gene; Foundations; Gene Targeting; Genes; Genetic; Genetic Translation; Genomic approach; Grant; Growth; Growth Factor; Human; Infection; Inflammation; Inflammatory; Insulin; Intestines; Malignant Neoplasms; Metabolic; Metabolism; Mitochondria; National Institute of General Medical Sciences; Natural regeneration; Organoids; Prevention; Proliferating; RNA Interference; Regenerative response; Research; Research Support; Resources; Signal Transduction; Stress; Testing; Tissue Engineering; Tissues; Translating; Work; cell growth; cell growth regulation; chronic inflammatory disease; clinically relevant; combat; cytokine; gastrointestinal epithelium; genetic approach; genomic tools; human disease; in vivo; intestinal epithelium; novel strategies; regenerative; response; stem cells; transcriptome sequencing; translation factor

PROJECT SUMMARY This MIRA/R35 application was conceived to replace R01 grants GM126033 and GM124434. These projects address the regulation of cell growth and proliferation, a central topic in cell and developmental biology that is relevant to the many human disorders in which cell growth is dysregulated (e.g. degenerative diseases, inflammatory conditions, cancers). Our NIGMS-supported research reaches back to 1994, with the singular objective to understand how cell proliferation is regulated in vivo, in the complex context of the animal body. Our research addresses fundamental issues: how growth signaling drives cell growth, how cell growth-associated metabolism regulates cell cycle progression, and how environmental, cellular and molecular interactions regulate growth signaling activities in vivo. We primarily utilize genetic approaches in Drosophila, with a current focus on intestinal epithelial renewal, but we also seize opportunities to translate our findings using human cells and organoids. Two of our projects are testing the unorthodox hypothesis that growth-dependent translation of mRNAs encoding limiting cell cycle regulators determines whether, and how fast, cells proliferate. We have validated this mechanism in Drosophila and human cells, and are currently investigating how upstream EGFR/RAS/ERK and Insulin/PI3K/mTOR signaling interface with the growth-dependent translation of factors that promote DNA replication (e.g. E2F1, CCNE2, CDC45). A third, related project will extend our discovery that EGFR/ERK signaling promotes mitochondrial biogenesis and a metabolic shift that activates cell growth and proliferation, in both Drosophila and human cells. New paradigms explaining how growth is coupled to cell division can present novel strategies and gene targets for the diagnosis, treatment, and prevention of common diseases involving dysregulated cell proliferation. Two final projects focus on how the Drosophila intestine senses and responds to damage. This is relevant to proliferative control because, for most epithelia, damage initiates a regenerative response that comprises growth signaling, stem cell activation, and regulated cell division. Epithelial damage responses also stimulate inflammation, giving further clinical relevance. To understand this regenerative response, genomics approaches (ATAC-seq, Cut&Tag, RNA-seq) will be used to identify the target genes of damage-dependent Cytokine/Jak/Stat signaling. In addition, we are conducting a unique, high-throughput functional screen using enterocyte-targeted RNAi’s to identify all of the Drosophila genes required to sense gut epithelial damage and initiate regeneration. A comprehensive catalog of the genes used in tissue damage responses will be a foundational resource for extending our understanding of stress- activated-, inflammatory-, and regenerative signaling. This will in turn present new approaches for: 1) controlling inflammation during infections and in auto-immune diseases, and: 2) stimulating regeneration to combat degenerative disease, and to aid tissue engineering.

项目概要 该 MIRA/R35 申请旨在取代 R01 拨款 GM126033 和 GM124434。这些项目 解决细胞生长和增殖的调节，这是细胞和发育生物学的一个中心主题 与细胞生长失调的许多人类疾病有关（例如退行性疾病、 炎症、癌症）。我们 NIGMS 支持的研究可以追溯到 1994 年， 目的是了解在动物体的复杂环境中细胞增殖是如何在体内调节的。我们的 研究解决了基本问题：生长信号如何驱动细胞生长，细胞生长如何相关 新陈代谢调节细胞周期进程，以及环境、细胞和分子相互作用如何调节 体内生长信号活动。我们主要在果蝇中利用遗传方法，目前的重点是 肠上皮更新，但我们也抓住机会利用人类细胞转化我们的发现 类器官。我们的两个项目正在测试非正统的假设，即生长依赖性翻译 编码限制性细胞周期调节因子的 mRNA 决定细胞是否增殖以及增殖速度。我们有 在果蝇和人类细胞中验证了这一机制，目前正在研究上游如何 EGFR/RAS/ERK 和胰岛素/PI3K/mTOR 信号传导接口与生长依赖性因子翻译 促进 DNA 复制（例如 E2F1、CCNE2、CDC45）。第三个相关项目将扩展我们的发现： EGFR/ERK 信号传导促进线粒体生物发生和代谢转变，从而激活细胞生长和 果蝇和人类细胞中的增殖。解释生长如何与细胞耦合的新范例 该部门可以为常见疾病的诊断、治疗和预防提出新的策略和基因靶​​点 涉及细胞增殖失调的疾病。最后两个项目重点关注果蝇肠道如何 感知损害并作出反应。这与增殖控制有关，因为对于大多数上皮细胞来说，损伤 启动再生反应，包括生长信号传导、干细胞激活和调节细胞 分配。上皮损伤反应也会刺激炎症，从而提供进一步的临床意义。到 了解这种再生反应，基因组学方法（ATAC-seq、Cut&Tag、RNA-seq）将用于 鉴定损伤依赖性细胞因子/Jak/Stat 信号传导的靶基因。此外，我们正在开展一项 独特的高通量功能筛选，使用肠细胞靶向 RNAi 来识别所有果蝇 感知肠道上皮损伤并启动再生所需的基因。基因的综合目录 用于组织损伤反应将成为扩展我们对压力的理解的基础资源 激活信号、炎症信号和再生信号。这反过来又会带来新的方法：1）控制 感染期间和自身免疫性疾病中的炎症，以及：2) 刺激再生以对抗 退行性疾病，并有助于组织工程。