Document text
Principal Investigator: Ian J Mohr
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2019
Award: $399,509
Funding agency: National Institute of General Medical Sciences
DESCRIPTION (provided by applicant): Regulation of gene expression at the level of translation allows both cells and organisms to respond swiftly to physiological stress and changing environments. Indeed, differential translation of capped, polyadenylated mRNAs by eukaryotic ribosomes plays a critical role in numerous biological processes vital for human health, including normal cell growth, differentiation and development, learning and memory, and the response to environmental stress, including virus infection. Viral model systems have proven to be particularly useful in elaborating cellular translational control strategies because their successful replication is absolutely dependent upon viral mRNA translation by host ribosomes. This investigation utilizes a herpesvirus family member, human cytomegalovirus (HCMV), to probe the complex circuitry regulating mRNA translation. Although innocuous in most healthy individuals, HCMV is a widespread, opportunistic pathogen responsible for severe disease among the immunocompromised, including bone marrow and solid organ transplant recipients along with AIDS patients. In addition, congenital HCMV infection is the leading viral cause of birth defects in newborns. Unlike many viruses that impair cellular protein synthesis, polyribosome formation is stimulated and host mRNA translation proceeds uninterrupted in human cytomegalovirus (HCMV)-infected cells. In addition to stimulating ribosome biogenesis and host translation factor accumulation, HCMV selectively controls cellular mRNA translation. While translation of some host mRNAs stimulates HCMV replication, others exemplified by the translation factor eIF6 effectively restrict productive viral growth. Our long-term overall objectie is to understand the mechanism(s) through which HCMV manipulates the cellular translational machinery.to control viral replication. Based on our preliminary results, we hypothesize that HCMV-induced changes to the cellular translational machinery globally impact host and viral mRNA translation to properly regulate productive viral growth. Here, this hypothesis is tested in three specific aims designed to i) determine the role of eIF6 in HCMV infection biology and understand its anti-viral activity; ii) investigate how ribosome biogenesis controls HCMV replication; and iii) determine how ribosome recycling and translation termination factors control gene expression in infected cells and thereby impact HCMV infection biology. As mRNA translation is critical for both productive HCMV replication and reactivation from latency, our investigation is likely to reveal new strategies for interfering with viral replication and creatin weakened, attenuated strains useful for vaccine development. In addition, these studies will provide insight into basic mechanisms of translational control that are important in many human diseases, including cancer and diabetes, where the regulation of protein production is abnormal.
Terms: <0-4 weeks old><ABCE1><ABCE1 gene><AIDS><ATP phosphohydrolase><ATPase><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunologic Deficiency Syndrome><Adenosine Triphosphatase><Adenosinetriphosphatase><Antiviral Agents><Antiviral Drugs><Antivirals><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Biogenesis><Biologic Models><Biological Function><Biological Models><Biological Process><Biology><Birth Defects><Bone Marrow><Bone Marrow Reticuloendothelial System><CMV><CMV infection><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Expansion><Cellular Growth><Complex><Congenital Abnormality><Congenital Anatomic Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Cytomegalic Inclusion Disease><Cytomegalovirus><Cytomegalovirus Infections><Cytoplasm><DNA-Dependent RNA Polymerase I><Data><Development><Diabetes Mellitus><Disease><Disorder><Environment><Family member><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><General Viruses><Generalized Growth><Genetic Transcription><Genetic Translation><Grafting Procedure><Growth><Growth Agents><Growth Factor><Growth Substances><Growth and Development><Growth and Development function><HCMV><HHV 5><HHV5><Health><Herpesviridae><Herpesviruses><Human><Human Herpesvirus 5><Humulin R><Immune system><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Impairment><Inclusion Disease><Individual><Insulin><Intracellular Communication and Signaling><Investigation><Learning><Malignant Neoplasms><Malignant Tumor><Memory><Messenger RNA><Model System><Modeling><Modern Man><Newborn Infant><Newborns><Normal Cell><Novolin R><Organ Transplantation><Organ Transplants><Organism><Organism-Level Process><Organismal Process><Origin of Life><Patients><Physiologic><Physiologic Processes><Physiological><Physiological Processes><Play><Pol I Transcription Initiation Complex Proteins><Pol1 Transcription Initiation Complex Proteins><Poly(A)+ mRNA><Polyadenylated mRNA><Polymerase><Polymerase 1 Complex Proteins><Polymerase I Complex Proteins><Polymerase I Complex Transcription Factors><Polyribosomes><Polysomes><Pre-rRNA><Production><Protein Biosynthesis><Proteins><Proteins Growth Factors><RNA Expression><RNA Polymerase A><RNA Polymerase I><RNA Polymerase I Transcription Factors><RNA, Ribosomal, Precursors><Recycling><Regular Insulin><Regulation><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Ribosomal RNA><Ribosomes><Role><Salivary Gland Virus Disease><Salivary Gland Viruses><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Stress><TFI Transcription Factors><Testing><Tissue Growth><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Translations><Transplant Recipients><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Genes><Viral Physiology><Virus><Virus Diseases><Virus Replication><allergic/immunologic body system><allergic/immunologic organ system><anti-viral agents><anti-viral drugs><anti-virals><base><biological signal transduction><cell growth><cytomegalovirus group><design><designing><develop a vaccine><development of a vaccine><developmental><diabetes><herpes virus><human disease><immunosuppressed patient><insight><living system><mRNA><mRNA Surveillance><mRNA Translation><malignancy><neoplasm/cancer><newborn child><newborn children><ontogeny><organ allograft><organ graft><organ xenograft><pathogen><polyadenylated messenger RNA><premature><prematurity><prevent><preventing><promoter><promotor><protein synthesis><public health relevance><rRNA><rRNA Precursor><reactivation from latency><release factor><response><ribosome recycling factor><ribosome releasing factor><social role><termination factor><transcription factor><translation factor><transplant patient><vaccine development><vaccine formulation><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease>