Translational regulation of tissue resident macrophages by GCN2

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

↗ Live URL (may be dead)

Document text

Principal Investigator: Soroush  Tahmasebi
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2024
Award: $470,106
Funding agency: National Heart Lung and Blood Institute

SUMMARY
mRNA translation, or protein synthesis, is a fundamental cellular process that can be dysregulated in several
human diseases. Macrophages are heterogeneous populations that are present in most tissues and adopt
tissue specific functions. The role of mRNA translational control in macrophages and in regards to their tissue
specific functions is not well understood. The broad goal of the proposed studies is to understand how
dysregulation of mRNA translation controls tissue-resident macrophage function during stress. The specific
goals of this study are to identify how GCN2 (general control nonderepressible 2)-dependent translational
control in macrophages affects macrophage function in RBC production and clearance and to uncover the
genes mediating this effect. The GCN2 is a serine/threonine-protein kinase that belongs to a signaling network
that coordinates cellular response to nutrient stress through translational regulator eIF2 (Eukaryotic translation
initiation factor 2). GCN2 senses amino acid levels and phosphorylates eIF2 in response to amino acid
deficiency. p-eIF2 inhibits global mRNA translation but paradoxically stimulates the translation of a subset of
key stress-response genes such as ATF4 (Activating Transcription Factor 4). Upregulation of stress-response
genes in response to GCN2/eIF2 signaling activates a transcription program that helps the cells to overcome
unfavorable conditions or undergo apoptosis. GCN2 function has been previously linked to important
physiological and pathological conditions such as memory formation, cancer and inflammatory diseases.
However, the role of GCN2 in regulating tissue-resident macrophages and their functions in RBC production
and clearance has not been characterized. Our current model suggests that GCN2 controls RBC production
and clearance during stress through regulation of mRNA translation in macrophages. Therefore, we propose
the following aims to achieve our goals: First we will determine the importance of GCN2 in RBC clearance by
macrophages (Aim 1) and define molecular mechanisms through which GCN2 impact this process. Next, we
will elucidate how GCN2 controls RBC maturation and production by macrophages (Aim 2). Finally, we will
examine how mechanical force sense by macrophage through GCN2 (Aim 3). To achieve these goals we will
use transgenic mice lacking GCN2 or carrying phospho-resistant eIF2 in macrophages and state-of-art
technology to study mRNA translation at genome-wide level. Our mouse models and in vivo and in vitro
experiments will rigorously assess the central role of macrophages in development of GCN2-dependent
defects during stress. Our genome-wide approach and in vitro functional analysis of selected targets will
discover novel translationally regulated genes downstream of GCN2 that play important roles in macrophage
regulation of RBC production during stress.

Terms: <ATF-4><Address><Adhesives><Adopted><Affect><Amino Acids><Animal Model><Animal Models and Related Studies><Apoptosis><Apoptosis Pathway><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding Proteins><Biochemical><Biomedical Engineering><Blood erythrocyte><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Cancers><Candidate Disease Gene><Candidate Gene><Cardiac><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><ChIP Sequencing><ChIP-seq><ChIPseq><Chicago><Collaborations><Consultations><Data><Defect><Development><Disease><Disorder><EIF-2 alpha><EIF-2alpha><EIF-2α><Erythroblasts><Erythrocytes><Erythrocytic><Erythrocytophagy><Erythroid><Erythrophagia><Erythrophagocytosis><Erythropoiesis><Eukaryotic Initiation Factors><Eukaryotic Peptide Initiation Factors><Eukaryotic Translation Initiation Factors><Ferroprotoporphyrin><Fetal Liver><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Goals><Heme><High Fat Diet><Homeostasis><IF2 Protein><In Vitro><Inflammatory><Initiation Factor-2><Intracellular Communication and Signaling><KI mice><KO mice><Kinases><Knock-in Mouse><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><Letters><Life Cycle><Life Cycle Stages><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Macrophage><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Marrow erythrocyte><Mechanical Stress><Mediating><Memory><Messenger RNA><Mice><Mice Mammals><Modeling><Molecular><Murine><Mus><Mφ><Normoblasts><Nucleated Erythrocytes><Nucleated red blood cell><Nucleated red cell><Null Mouse><Nutrient><Pathologic><Pathway interactions><Peptide Initiation Factor 2><Peptide Initiation Factor IF-2><Phagocytes><Phagocytic Cell><Phagocytosis><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Physiological Homeostasis><Piezo 1><Piezo 1 ion channel><Piezo1><Play><Population Heterogeneity><Process><Production><Programmed Cell Death><Prokaryotic Initiation Factor-2><Protein Binding><Protein Biosynthesis><Protein Phosphorylation><Protein-Serine Kinase><Protein-Serine-Threonine Kinases><Protein-Threonine Kinase><Protoheme><RNA Expression><Red Blood Cells><Red Cell><Regulation><Resistance><Resolution><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomes><Role><Scientist><Seminal><Serine Kinase><Serine-Threonine Kinases><Serine/Threonine Protein Kinase Gene><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Subcellular Process><Techniques><Technology><Testing><Threonine Kinase><Time><Tissue Engineering><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Translation Initiation><Translational Initiation Factor 2><Translational Regulation><Translations><Transphosphorylases><Universities><Up-Regulation><Upregulation><activating transcription factor 4><alpha Subunit Eukaryotic Initiation Factor 2><amebocyte><aminoacid><bio-engineered><bio-engineers><bioengineered tissue><bioengineering><biological adaptation to stress><biological engineering><biological signal transduction><blood corpuscles><bound protein><cell type><chromatin immunoprecipitation-sequencing><computer based prediction><consultation><developmental><diverse populations><engineered tissue><erythroid development><experience><experiment><experimental research><experimental study><experiments><ferroheme><gene network><genome scale><genome-wide><genomewide><heterogeneous population><human disease><in vivo><infB Gene Product><infB Protein><inhibitor><innovate><innovation><innovative><invention><knockin mice><life course><mRNA><mRNA Translation><malignancy><mechanical force><model of animal><mouse model><murine model><neoplasm/cancer><novel><nucleated RBCs><pathogen><pathway><population diversity><predictive modeling><programs><protein synthesis><reaction; crisis><resistant><resolutions><response><social role><stress response><stress; reaction><tissue repair><transcription factor><translation><translatome>