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：
10630233
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/10630233
关键词：
A549 Address Aging Anabolism Apoptosis Binding Biochemical Biological Biology Biomass CRISPR/Cas technology Cell Cycle Arrest Cell Survival Cells Chemicals Clinic Clinical Complex Consumption DNA Methylation DNMT3a Data Development Diabetes Mellitus Disease Drug Targeting Environment Enzymes Epigenetic Process Essential Amino Acids Exhibits FRAP1 gene Genetic Genetic Transcription Glucose Glutamine Goals Growth Growth Factor Hela Cells Homeostasis Human Human Cell Line Immunosuppression Introns Isotope Labeling 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 Proliferating Protein Biosynthesis Proteins Proteomics RNA RNA Interference RNA methylation Reaction Regulation Reporting Ribosomal RNA Role S-Adenosylhomocysteine S-Adenosylmethionine Signal Pathway Signal Transduction Syndrome System Therapeutic Therapeutic Intervention Tissues Tracer Transcriptional Regulation c-myc Genes cell growth cell motility 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）的机械目标感官并整合了多种环境信号控制能量和营养耗尽的生物合成过程，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的生长导致大分子合成增加是增加细胞生物量启动细胞的先决条件增长和分裂。在许多疾病中，MTORC1信号的突出性增强了考虑在包括神经退行性疾病，糖尿病的几种疾病中靶向MTORC1信号传导，肿瘤综合征和衰老。但是，直接MTORC1针对疗法，在概念上和临床上是一个有希望的目标，仅在人类患者中显示出有限的疗效。因此，更好地理解 MTORC1下游的生物学以及开发更有效，更具体的治疗策略需要治疗MTORC1驱动的疾病。达到伴随的生物合成需求增殖，细胞必须增加养分从环境中的运输。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率的主要营养素。一个新兴的方面养分在衰老和增殖性疾病中的利用包括饮食中蛋氨酸的作用，最近在肥胖，代谢综合征和癌症的背景下进行了探讨。蛋氨酸是必不可少的分解代谢和回收的氨基酸以一系列代谢反应指定为蛋氨酸循环。通过蛋氨酸和ATP转化为通用的甲基供体S-腺苷甲硫代（SAM）蛋氨酸腺基转移酶2α（MAT2A）酶。根据该提议，我们建议研究 MTORC1信号传导对S-腺苷甲氨酸（SAM）合成的影响和随后的甲基化支持合成代谢的过程。我们已经确定MTORC1刺激了SAM合成通过C-MYC对MAT2A表达的直接转录控制各种细胞设置。我们建议评估MTORC1信号传导对各种人类细胞中SAM合成的影响（特定AIM1）。将要确定MTORC1信号促进RNA甲基化的机制，尤其是N6-- 甲基腺苷（M6A）标记。我们将确定M6A在对照中MTORC1下游RNA上的作用细胞生长（特定AIM2）。此外，我们将确定MTORC1-MAT2A轴对肿瘤生长和从这种机制得出的潜在治疗策略（特定的AIM3）。因此，该建议的总体目标是破译MTORC1控制RNA的分子机制在正常和病理环境中的甲基化。我们预计拟议的研究将产生新的见解 SAM水平如何改变合成代谢的代谢，并将发现治疗靶点以扰动mTORC1驱动疾病。