Document text
Principal Investigator: Issam Ben-Sahra
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $320,000
Funding agency: National Institute of General Medical Sciences
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.
Terms: <A549><ATP-Methionine S-Adenosyltransferase><Address><Ademetionine><AdoMet><Aging><Anabolism><Apoptosis><Apoptosis Pathway><Autoregulation><Binding><Biochemical><Biological><Biology><Biomass><Body Tissues><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancers><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Cycle Arrest><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Expansion><Cellular Growth><Chemicals><Clinic><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><Consumption><D-Glucose><DNA Methylation><DNMT3a><Data><Degenerative Neurologic Disorders><Development><Dextrose><Diabetes Mellitus><Disease><Disorder><Drug Targeting><EC 2.1.1><Environment><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Essential Amino Acids><Exhibits><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Gene Transcription><Generalized Growth><Genetic><Genetic Transcription><Gln><Glucose><Glutamine><Goals><Growth><Growth Agents><Growth Factor><Growth Substances><HeLa><Hela Cells><Homeostasis><Human><Human Cell Line><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Intermediary Metabolism><Intervening Sequences><Intracellular Communication and Signaling><Introns><Isotope Labeling><Kinases><L-Glutamine><Link><Lipids><MEL><MEL Gene><MEL Transforming Oncogene Homolog><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Measures><Mechanistic Target of Rapamycin><Melanocyte Transforming Oncogene Homolog><Messenger RNA><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolic syndrome><Metabolism><Methionine><Methionine Metabolism><Methionine Metabolism Pathway><Methylation><Methyltransferase><Modern Man><Modification><Molecular><Molecular Interaction><Motility><Mutate><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Non-Polyadenylated RNA><Nucleotide Synthesis><Nutrient><Obesity><Organ><PC-3><PC-3 cell line><PC3><PC3 cell line><Pathologic><Pathway interactions><Patients><Phosphorylation Site><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Physiological Homeostasis><Position><Positioning Attribute><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Process><Programmed Cell Death><Proliferating><Protein Biosynthesis><Proteins><Proteins Growth Factors><Proteomics><Purines/Pyrimidines/Nucleotides/Nucleic Acids Metabolism><Q Levoglutamide><Q. Levoglutamide><RAB8><RAB8 Homolog><RAFT1><RNA><RNA Expression><RNA Gene Products><RNA Interference><RNA Silencing><RNA methylation><RNAi><Reaction><Recycling><Regulation><Reporting><Ribonucleic Acid><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomal RNA><Role><S-Adenosylhomocysteine><S-Adenosylmethionine><S-Adenosylmethionine Synthetase><S-adenosyl methionine><S-adenosyl-methionine><SAMe><Sequence-Specific Posttranscriptional Gene Silencing><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Syndrome><System><Therapeutic><Therapeutic Intervention><Tissue Growth><Tissues><Tracer><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transphosphorylases><Tumor Cell><adiposity><biologic><biological signal transduction><biosynthesis><c myc><c-myc Genes><cell growth><cmyc><corpulence><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><diabetes><dietary><drug discovery><epigenetically><hDNA methyltransferase 3a><histone methylation><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><inhibitor><insight><intervention therapy><mRNA><mTOR><macromolecule><malignancy><mammalian target of rapamycin><metabolic rate><metabolism measurement><metabolomics><metabonomics><methionine adenosyltransferase><methylase><mouse model><murine model><neoplasm/cancer><neoplastic cell><neurodegenerative illness><neurological disease><novel><nucleotide metabolism><ontogeny><pathway><pre-clinical><preclinical><protein synthesis><rRNA><s-adenosyl-l-methionine><side effect><social role><stable isotope><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><transmethylase><tumor><tumor growth><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog>