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Principal Investigator: Charles Bou-Nader
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $249,000
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
The proposed research seeks to elucidate the structural and mechanistic basis of RNA-dependent innate
immune antiviral proteins regulation that stop translation to curb viral infection. The proposal employs a
synergistic combination of structural biology (X-ray crystallography, cryo-EM), biochemical analyses (kinase,
RNA cleavage assay) and biophysical methods (fluorescence polarization, smFRET, calorimetry) to understand
how viral RNA structures inhibit the double-stranded RNA activated protein kinase R (PKR, Aim 1) and the 2´-
5´-oligoadenylate synthases/endoribonuclease RNase L pathway (Aim 2) to escape the immune response, as
well as the mechanism of interferon induced protein with tetratricopeptide 1 (IFIT1) induced translation control
(Aim 3). Completion of the proposed research will not only produce critical insights into host-virus interplay and
host translation control, but will also reveal novel principles of riboregulation. Such in-depth mechanistic
understanding will provide a solid foundation for future work to design functional RNA devices that elicit specific
functions of PKR and OAS/RNase L, with potential applications in the treatment of infectious and autoimmune
and inflammatory diseases that are severe and costly threats to public health. Upon transition to independence,
the research findings from this proposal will form the basis of the candidate’s first R01 funding application.
The candidate seeks to acquire additional mentored research and career development training through a detailed
plan tailored to his specific training deficiencies and proposed research outside of his current expertise. Such
requested training in the mentored phase, wholly funded by the NIH Division of Intramural Research, will enable
him to become a successful principal investigator upon his transition into research independence. The K99-R00
award will provide excellent opportunities for the candidate to acquire concepts and research skills new to him
through a combination of formal course work, hands-on training, and frequent discussions and evaluations with
his co-mentoring team formed of five internationally renowned intramural and extramural scientists. The major
new research skills to be acquired include cryo-EM, smFRET and eukaryotic protein expression. In consultation
with his mentors and advisors, the candidate has developed a detailed career development plan that is tailored
to remedy his specific deficiencies in teaching, mentoring, lab management, and career development skills. The
plan includes a mentoring course followed by mentoring a NIDDK post-baccalaureate assigned to him, a
leadership and management course, and systematic trainings in career development skills including career
counseling and assessment, mock interviews, practice job and chalk talks.
Terms: <Adenoviridae><Adenoviruses><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Architecture><Assay><Autoimmune Diseases><Award><Base Pairing><Binding><Bioassay><Biochemical><Biological Agent><Biological Assay><Biological Products><Calorimetry><Career Counseling><Career Guidance><Cellular Stress><Cellular Stress Response><Chalk><Chronic Disease><Chronic Illness><Complex><Consultations><Cryo-electron Microscopy><Cryoelectron Microscopy><Crystallographies><Crystallography><DAI Protein Kinase><DSRNA-Dep Protein Kinase><Development Plans><Development and Research><Devices><Disease><Disorder><Double Stranded RNA-Dependent eIF-2 alpha Protein Kinase><Double-Stranded RNA><EIF2AK1><EXTMR><Educational process of instructing><Electron Cryomicroscopy><Elements><Endoribonucleases><Engineering / Architecture><Eukaryotic Initiation Factor 2alpha Kinase><Evaluation><Extramural><Extramural Activities><Fluorescence Polarization><Foundations><Functional RNA><Funding><Future><Gene Transcription><Genetic Diversity><Genetic Transcription><Genetic Variation><Genetics-Mutagenesis><HIV-1><HIV-I><HIV1><Heme Controlled Repressor><Heme-Controlled Inhibitor><Heme-Controlled Translational Repressor><Heme-Regulated eIF-2alpha Kinase><Hemin Controlled Repressor><Hemin-Controlled Translational Repressor><Host Factor><Host Factor Protein><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Human poliovirus><IFN><Immune><Immune response><Immunes><Immunological response><In Vitro><Infection><Inflammatory><Innate Immune Response><Innate Immunity><Institution><Integration Host Factors><Interferon-Induced Double-Stranded RNA-Activated Protein Kinase><Interferon-Inducible Double Stranded RNA Dependent Protein Kinase><Interferon-Inducible RNA-Dependent Protein Kinase><Interferon-Inducible elF2Alpha Kinase><Interferons><International><Interview><Intramural Research><Investigators><Isoforms><Jobs><Kinases><Knowledge><Leadership><Lentivirinae><Lentivirus><Link><Maps><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Mentors><Messenger RNA><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mutagenesis><Mutagenesis Molecular Biology><NIDDK><NIH><National Institute of Diabetes and Digestive and Kidney Diseases><National Institutes of Health><Native Immunity><Natural Immunity><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-Specific Immunity><Non-translated RNA><Noncoding RNA><Nonspecific Immunity><Nontranslated RNA><Nucleic Acids><Occupational Guidance><Occupations><P1/eIF2A Protein Kinase><P68 Protein Kinase><PRKR><PRKR gene><Pathway interactions><Phase><Phosphates><Phosphotransferase Gene><Phosphotransferases><Polio Virus><Poliovirus><Position><Positioning Attribute><Postbaccalaureate><Predisposition><Principal Investigator><Professional Positions><Protein Binding Domain><Protein Binding Motif><Protein Biochemistry><Protein Inhibition><Protein Isoforms><Protein Kinase PKR><Protein-Protein Interaction Domain><Protein/Amino Acid Biochemistry><Proteins><Public Health><Putative RNA-Binding Region><R & D><R&D><RNA><RNA Activated Protein Kinase><RNA Binding Domain><RNA Decay><RNA Expression><RNA Gene Products><RNA Nucleases><RNA Recognition Motif><RNA Splicing><RNA endonuclease><RNA-Dependent Protein Kinase><RNP Domain><RNP Motif><RNP-1 Signature><RNase><Regulation><Research><Research Personnel><Researchers><Resistance><Ribonuclease Family Protein><Ribonucleases><Ribonucleic Acid><Risk Factors><Scientist><Secure><Self-Phosphorylating Protein Kinase><Single Crystal Diffraction><Site><Solid><Spinal Column><Spine><Splicing><Stress><Structure><Susceptibility><TIK Kinase><Teaching><Testing><Training><Transcript><Transcription><Translation Initiation><Translational Inhibition><Translational Repression><Translations><Transphosphorylases><United States National Institutes of Health><Untranslated RNA><Vertebral column><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Gene Products><Viral Gene Proteins><Viral Genome><Viral Physiology><Viral Proteins><Virus><Virus Diseases><Virus Inhibitors><Virus Replication><Vocational Counseling><Vocational Guidance><Work><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><arms race><autoimmune condition><autoimmune disorder><autoimmunity disease><backbone><biologics><biopharmaceutical><biophysical analysis><biophysical approaches><biophysical methodology><biophysical methods><biophysical studies><biophysical techniques><biotherapeutic agent><career counselor><career development><cell stress><chronic disorder><conformation><conformational><conformational state><conformationally><conformations><consultation><cost><crosslink><cryo-EM><cryoEM><cryogenic electron microscopy><design><designing><dsRNA><dsRNA-Activated Inhibitor><eIF-2 Kinase><eIF-2 Recycling Factor eRF><eIF-2alpha Kinase><executive coaching><host response><immune system response><immunogenicity><immunoresponse><infectious disease treatment><inhibit protein><inhibit proteins><inhibitor><inorganic phosphate><insight><mRNA><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><noncoding><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><nuclease><oligoadenylate><p65 Kinase><p68 Kinase><pathway><phosphodiester><poliomyelitis virus><postbac><postbacc><protein expression><protein function><protein inhibitions><protein kinase R><protein protein interaction><reconstitute><reconstitution><research and development><resistant><single-molecule FRET><single-molecule fluorescence resonance energy transfer><skill acquisition><skill development><skills><smFRET><structural biology><tenure process><tenure track><tool><translation><translation factor><triphosphate><tripolyphosphate><viral RNA><viral infection><viral inhibitor><viral multiplication><viral replication><virus RNA><virus genome><virus infection><virus multiplication><virus protein><virus-induced disease>