Project 1- Micro-RNA-dependent signaling by the UPR

项目 1 - UPR 的 Micro-RNA 依赖性信号传导

• 批准号: 10247660
• 负责人: John Alan Diehl
• 金额: $ 29.17万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247660
• 关键词: ARNTL gene; Address; Apoptosis; Apoptotic; B-Cell Lymphomas; Blood Vessels; Cell Cycle Progression; Cell Death; Cell Fate Control; Cell Survival; Cell division; Cells; Collaborations; Data; Defect; Development; EZH2 gene; Endoplasmic Reticulum; Foundations; Funding; Gene Expression; Genetic Transcription; Genetic Translation; Glucose; Growth; Growth Factor; Homeostasis; Human; IFNAR1 gene; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediator of activation protein; Messenger RNA; Metabolic; MicroRNAs; Modeling; Molecular; Molecular Chaperones; Normal Cell; Nutrient; Organism; Oxygen; Pathway interactions; Proliferating; Property; Protein Biosynthesis; Proteins; Regulation; Repression; Role; Signal Transduction; T-Lymphocyte; Testing; Tissues; Translational Regulation; Translations; Tumor Volume; Work; anti-cancer; biological adaptation to stress; cancer cell; cancer therapy; cell growth; circadian; circadian pacemaker; cyclin G1; defined contribution; deprivation; design; endoplasmic reticulum stress; experimental study; glucose metabolism; misfolded protein; neoplastic cell; novel; prevent; protein metabolism; response; small molecule inhibitor; stem; transcription factor; transcription factor CHOP; tumor; tumor metabolism; tumor progression; tumorigenesis

Abstract Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. In normal cells, limits in nutrient availability trigger growth arrest and/or apoptosis thereby preventing cellular expansion under such conditions. Our scientific premise is that the pro-survival activities of PERK reflect the combined impact of PERK-dependent differential control of protein synthesis and gene expression. In the previous funding cycle, we identified miR-211 and miR-216b as a PERK-ATF4 regulated micro-RNAs that regulate cell survival. We identified three critically important miR-211 targets. The first is the pro-apoptotic transcription factor, Chop. The second target is the Bmal1-Clock heterodimeric transcription factor that functions as the primary driver of circadian gene expression and thus circadian oscillation. Both Bmal1 and Clock are direct targets of miR-211 and are repressed by miR-211 during a UPR. Through analysis of PERK-miR-211 regulation of Bmal1 and the circadian clock, we discovered that 1) circadian gene expression is disrupted by the UPR, 2) Bmal1 loss contributes to PERK-dependent regulation of mRNA translation. We propose a hypothesis wherein the UPR inducible micro-RNAs (miR- 211, miR-217) regulate cell fate by silencing key targets such as Bmal1 which thereby contributes to PERK- dependent translational regulation and cell survival. To address this hypothesis, we propose three specific aims. Aim 1, will defined the critical targets of PERK-miR211-Bmal1 regulation and their contribution to cell survival. Aim 2 will define the role of miR-217 in antagonizing miR-211 regulation of its transcriptional targets. Aim 3 will define the role of miR-211-dependent regulation of Bmal1 to the development and progression of B-cell lymphoma. There are obvious points of cross-talk between this proposal and Project 2 which focuses on how the UPR antagonizes myc induced apoptosis and ATF4-dependent regulation of tumor cell metabolism. Through collaboration with Project 2, we will assess the role of miR-211 and Bmal1 as a mediator of tumor cell metabolism and survival. Through collaboration with Project 3, we will determine how miR-211, miR-217 and Bmal1 regulate IFNAR1 signaling and regulation in cytotic T- lymphocytes. The findings steming from work proposed herein will provide a foundation for the design of novel anti-cancer therpeutics.

抽象的 快速增殖的癌细胞必须在微环境中繁衍生息，其中代谢营养素（例如 随着肿瘤体积的扩展，葡萄糖，氧和生长因子成为限制 组织的血管性。在正常细胞中，养分可用性的限制触发生长停滞和/或凋亡 从而防止在这种情况下细胞扩张。我们的科学前提是亲生 PERK的活性反映了蛋白质合成的PERK依赖性差分控制的综合影响 和基因表达。在上一个资金周期中，我们将miR-211和miR-216b确定为PERK-ATF4 调节调节细胞存活的微RNA。我们确定了三个至关重要的miR-211靶标。 第一个是促凋亡转录因子，切碎。第二个目标是BMAL1-CLOCK异二聚体 作为昼夜节律表达的主要驱动力的转录因子，因此 振荡。 BMAL1和时钟都是miR-211的直接靶标，在A期间被miR-211抑制 UPR。通过分析BMAL1和昼夜节律的PERK-MIR-211调节，我们发现 1）昼夜节律基因表达受到UPR的破坏，2）BMAL1损失有助于PERK依赖性 mRNA翻译的调节。我们提出了一个假设，其中UPR诱导的微RNA（mir-- 211，miR-217）通过沉默的关键靶标（例如BMAL1）来调节细胞命运，从而有助于振作 依赖的翻译调节和细胞存活。为了解决这一假设，我们提出了三个特定的 目标。 AIM 1将定义PERK-MIR211-BMAL1调节的关键目标及其对细胞的贡献 生存。 AIM 2将定义miR-217在拮抗其转录的调节中的作用 目标。 AIM 3将定义miR-211依赖性BMAL1对开发的作用 B细胞淋巴瘤的进展。该提案与项目2之间有明显的串扰 该重点是UPR如何拮抗Myc诱导的凋亡和ATF4依赖性调节 肿瘤细胞代谢。通过与项目2的合作，我们将评估miR-211和BMAL1的作用 作为肿瘤细胞代谢和生存的介体。通过与项目3的合作，我们将 确定miR-211，miR-217和BMAL1如何调节IFNAR1信号传导和细胞t-中的调节 淋巴细胞。源于本文提出的工作的发现将为设计提供基础 新颖的抗癌治疗学。