Control of RNA methylation by growth signals through the mTORC1 pathway

通过 mTORC1 途径通过生长信号控制 RNA 甲基化

基本信息

批准号：
10469579
负责人：
Issam BEN-SAHRA
金额：
$ 32万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10469579
关键词：
A549 Address Aging Anabolism Apoptosis Binding Biochemical Biological Biology Biomass CRISPR/Cas technology Cell Cycle Arrest Cell Proliferation Cell Survival Cells Clinic Clinical Complex Consumption DNA Methylation DNA Modification Methylases Data Development Diabetes Mellitus Disease Drug Targeting Environment Enzymes Epigenetic Process Essential Amino Acids Exhibits FRAP1 gene Genetic Transcription Glucose Glutamine Goals Growth Growth Factor Hela Cells Homeostasis Human Human Cell Line Immunosuppression Introns Isotope Labeling Lead Link Lipids MEL Gene Malignant Neoplasms Mammalian Cell Measures Messenger RNA Metabolic Metabolic Pathway Metabolic syndrome Metabolism Methionine Methionine Metabolism Pathway Methylation Methyltransferase Modification Molecular Mutate Neurodegenerative Disorders Nutrient Obesity Organ PC3 cell line Pathologic Pathway interactions Patients Phosphorylation Site Phosphotransferases Physiological Positioning Attribute Process Protein Biosynthesis Proteins Proteomics RNA RNA Interference RNA methylation Reaction Regulation Reporting Ribosomal RNA Role S-Adenosylmethionine Signal Pathway Signal Transduction Syndrome System Therapeutic Therapeutic Intervention Tissues Tracer Transcriptional Regulation base c-myc Genes cell growth cell motility chemical genetics dietary drug discovery histone methylation inhibitor insight macromolecule metabolic rate metabolomics methionine adenosyltransferase mouse model neoplastic cell nervous system disorder novel nucleotide metabolism pre-clinical side effect stable isotope targeted treatment therapeutic target tumor tumor growth

项目摘要

SUMMARY The mechanistic target of rapamycin complex 1 (mTORC1) senses and integrates diverse environmental signals to control energy and nutrient-consuming biosynthetic processes, such as protein, lipid, and nucleotide synthesis. mTORC1 stimulates anabolic cell growth through posttranslational and transcriptional mechanisms leading to increased macromolecule synthesis a prerequisite to augment cellular biomass priming cells for growth and division. In many diseases, the prominence of mTORC1 signaling reinforces the importance of considering targeting mTORC1 signaling in several diseases including neurodegenerative disorders, diabetes, tumor syndromes, and aging. However, direct mTORC1 targeted therapies, being conceptually and preclinically a promising target, displayed only limited efficacy in human patients. Therefore, a better understanding of the biology downstream of mTORC1 and the development of more effective and specific therapeutic strategies in the treatment of mTORC1-driven diseases are needed. To achieve the biosynthetic demands accompanying proliferation, cells must increase the transport of nutrients from the environment. Glucose, lactate, and glutamine are the principal nutrients that promote biosynthesis and survival in mammalian cells. An emerging aspect of nutrient utilization in aging and proliferative diseases includes the role of dietary methionine restriction, which was recently explored in the context of obesity, metabolic syndrome, and cancer. Methionine is an essential amino acid that is catabolized and recycled in a sequence of metabolic reactions designated as the methionine cycle. Methionine and ATP are converted into the universal methyl donor S-adenosylmethionine (SAM) via the methionine adenosyltransferase 2 alpha (MAT2A) enzyme. Under this proposal, we propose to study the influence of mTORC1 signaling on S-adenosylmethionine (SAM) synthesis and the subsequent methylation processes supporting anabolic metabolism. We have identified that mTORC1 stimulates SAM synthesis in various cell settings through direct transcriptional control of MAT2A expression by c-MYC. We propose to evaluate the influence of mTORC1 signaling on SAM synthesis in a variety of human cells (Specific Aim1). Will identify the mechanisms by which mTORC1 signaling promotes RNA methylation, particularly the N6- methyladenosine (m6A) mark. We will determine the role of m6A on RNA downstream of mTORC1 in the control of cell growth (Specific Aim2). Furthermore, we will determine the implication of the mTORC1-MAT2A axis on tumor growth and the potential therapeutic strategy derived from this mechanism (Specific Aim3). Thus, the overall goal of this proposal is to decipher the molecular mechanisms by which mTORC1 controls RNA methylation in normal and pathological settings. We anticipate that the proposed studies will yield new insights into how SAM levels alter anabolic metabolism and will uncover therapeutic targets to perturb mTORC1-driven diseases.

概括雷帕霉素复合物 1 (mTORC1) 的机制靶点感知并整合不同的环境信号控制能量和营养消耗的生物合成过程，例如蛋白质、脂质和核苷酸合成。 mTORC1 通过翻译后和转录机制刺激合成代谢细胞生长导致大分子合成增加，这是增加细胞生物量的先决条件，启动细胞生长和分裂。在许多疾病中，mTORC1 信号传导的重要性凸显了考虑在多种疾病中靶向 mTORC1 信号传导，包括神经退行性疾病、糖尿病、肿瘤综合征和衰老。然而，直接的 mTORC1 靶向疗法在概念上和临床前都处于一个有希望的目标，但在人类患者中仅显示出有限的疗效。因此，更好地了解 mTORC1 的生物学下游以及更有效和更具体的治疗策略的开发需要治疗 mTORC1 驱动的疾病。为了实现伴随的生物合成需求增殖时，细胞必须增加从环境中输送营养物质。葡萄糖、乳酸和谷氨酰胺是促进哺乳动物细胞生物合成和存活的主要营养素。一个新兴的方面衰老和增殖性疾病中的营养利用包括饮食蛋氨酸限制的作用，这最近在肥胖、代谢综合征和癌症的背景下进行了探索。蛋氨酸是人体必需的在一系列代谢反应中被分解代谢和再循环的氨基酸，称为蛋氨酸循环。甲硫氨酸和 ATP 通过以下途径转化为通用甲基供体 S-腺苷甲硫氨酸 (SAM) 甲硫氨酸腺苷转移酶 2 α (MAT2A) 酶。根据这项建议，我们建议研究 mTORC1 信号传导对 S-腺苷甲硫氨酸 (SAM) 合成和随后甲基化的影响支持合成代谢的过程。我们发现 mTORC1 刺激 SAM 合成通过 c-MYC 对 MAT2A 表达的直接转录控制来调节各种细胞设置。我们建议评估 mTORC1 信号传导对多种人类细胞中 SAM 合成的影响（具体目标 1）。将要确定 mTORC1 信号传导促进 RNA 甲基化的机制，特别是 N6- 甲基腺苷 (m6A) 标记。我们将在对照中确定 m6A 对 mTORC1 RNA 下游的作用细胞生长（具体目标2）。此外，我们将确定 mTORC1-MAT2A 轴对肿瘤生长以及源自该机制的潜在治疗策略（具体目标3）。因此，该提案的总体目标是破译 mTORC1 控制 RNA 的分子机制正常和病理情况下的甲基化。我们预计拟议的研究将产生新的见解研究 SAM 水平如何改变合成代谢，并将揭示扰乱 mTORC1 驱动的治疗靶点疾病。