Co-translational Regulation in the Vasculature of Organ Systems with Aging
Document text
Principal Investigator: PAUL H GOLDSPINK Organization: UNIVERSITY OF ILLINOIS AT CHICAGO Fiscal Year: 2024 Award: $199,875 Funding agency: National Institute on Aging Project Summary/Abstract The production of functional proteins is a multistep process whereby newly synthesized polypeptides are enzymatically processed, folded, and assembled into oligomeric complexes. Key maturation processes occur co-translationally by coupling mRNA translation and nascent protein maturation on the ribosomes, assisted by a network of regulatory proteins. Despite decades of basic research, our understanding of co-translational processes is shaped predominantly by genetic manipulations in prokaryotic and eukaryotic cell models, but limited data exists in cells from intact mammalian physiological systems. To overcome this hurdle, this project aims to develop a comprehensive understanding of co-translational regulation of nascent proteins as they reach their functional state within the angiogenic signaling pathways of the endothelium in the heart during aging. We have recently developed an approach and tested the potential for simultaneous isolation of proteins present within the actively translating polyribosome/mRNA complexes within the endothelium of the heart. State-of-the-art multiplex labelling and quantification of these proteins has permitted the identification of concordant and discordant regulated cell-specific pathways based on actively translating mRNA and protein profiles associated with the endothelial stress. Leveraging this innovative advancement in “functional co- translatomics”, we aim to study the changes in co-translational complexes within endothelial cell angiogenic ligand-receptor and cell-cell interaction signaling networks within the aging heart. In Aim 1 , we will define changes in the co-translational regulation of concordantly regulated angiogenic signaling pathways during neonatal and adult life with aging and gender. In Aim 2 , we will define the post-translational modifications of proteins within discordantly regulated angiogenic signaling pathways which may contribute to the impairment angiogenesis in the heart during aging. Ultimately this knowledge could aid in the development of more effective means for diagnosing and treating the impairment of angiogenesis that occurs with aging and predisposes the heart to cardiovascular disease and injury. Terms: <21+ years old><Adult><Adult Human><Affinity Chromatography><Age><Aging><Apoplexy><Basic Research><Basic Science><Blood capillaries><Body System><Brain Vascular Accident><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Isolation><Cell Line><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell model><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cell-to-Cell Interaction><CellLine><Cells><Cellular model><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chaperone><Characteristics><Complex><Coronary><Coupling><Data><Data Set><Development><Diagnosis><Embryo Development><Embryogenesis><Embryonic Development><Endothelial Cells><Endothelium><Environment><Enzyme Gene><Enzymes><Eukaryotic Cell><Event><Gender><Gene Expression><Gene Transcription><Generalized Growth><Genetic Transcription><Genomics><Goals><Gonadal Steroid Hormones><Growth><Heart><Heart Vascular><Hypertension><Impairment><Intracellular Communication and Signaling><Investigation><Knowledge><Label><Life><Ligands><Maintenance><Mammalian Cell><Mediating><Mediator><Messenger RNA><Molecular><Molecular Chaperones><Myocardial Infarct><Myocardial Infarction><Neonatal><Organ><Organ System><Organism><Pathologic><Pathology><Pathway interactions><Physiologic><Physiological><Play><Polyribosomes><Polysomes><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Post-Translational Regulation><Posttranslational Modifications><Posttranslational Protein Processing><Posttranslational Regulation><Process><Production><Prokaryotae><Prokaryotic Cells><Protein Modification><Proteins><Proteome><Proteomics><RNA Expression><Receptor Protein><Regulation><Regulatory Protein><Ribosomes><Role><Scheme><Sex Hormones><Sex Steroid Hormones><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><Strains Cell Lines><Stress><Stroke><System><Technology><Testing><Tissue Growth><Transcript><Transcription><Translating><Translational Regulation><Translations><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Wound Repair><Yeasts><adulthood><affinity purification><age associated alterations><age associated changes><age associated disease><age associated disorder><age associated impairment><age correlated alterations><age correlated changes><age dependent alterations><age dependent changes><age dependent disease><age dependent disorder><age dependent impairment><age related alterations><age related changes><age related human disease><age specific alterations><age specific changes><age-related disease><age-related disorder><age-related impairment><ages><aging associated><aging related><alterations with age><angiogenesis><biological signal transduction><brain attack><capillary><cardiac aging><cardiac infarct><cardiovascular disorder><cardiovascular injury><cell sorting><cell type><cerebral vascular accident><cerebrovascular accident><changes with age><circulatory system><coronary attack><coronary infarct><coronary infarction><cultured cell line><developmental><gender difference><gender-associated difference><gene manipulation><genetic manipulation><genetic regulatory protein><genetically manipulate><genetically perturb><global gene expression><global transcription profile><gonadal steroids><heart aging><heart attack><heart infarct><heart infarction><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><in vivo><injury response><innovate><innovation><innovative><intercellular communication><living system><mRNA><mRNA Translation><novel><ontogeny><pathway><polypeptide><postnatal><prokaryote><protein homeostasis><proteostasis><receptor><regulatory gene product><response><response to injury><sex><sex steroid><social role><stroked><strokes><transcriptome><transcriptomics><translation><wound healing><wound recovery><wound resolution>