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Principal Investigator: Frederic D Bushman
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $167,770
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY- CORE B (GENOMICS CORE)
Core B (Genomics Core) will provide key support to the mVACS team in Clostridioides difficile genome sequence
analysis, antigen design, microbiome sequence analysis, routine statistical analysis, and high content data
management. Core B will use advanced genomics-based methods to quantify C. difficile genome composition
and genetic variation, and associate these with outcomes. Core B will support analysis of protein structure to
allow expression of well-folded domains as mRNAs. Core B will characterize DNA inversion systems and other
mechanisms of DNA modification and alterations in gene activity that may impact vaccine efficacy. Core B will
also carry out transcriptional profiling on C. difficile isolated from the intestine of vaccinated and immunodeficient
mice, to assess how C. difficile responds in vivo to effective and ineffective immune responses. The Aims of
Core B are: (1) C. difficile genomics to identify optimal targets for modified mRNA vaccines. Long read and short
read data will be merged to generate complete assemblies, as in our previous work. Gene content will be
enumerated and compared with clinical outcomes. (2) To assess variation in sequence and abundance of C.
difficile vaccine targets. C. difficile isolates are known to encode considerable variation in their surface proteins.
In addition, DNA inversion systems encode on-off switches affecting surface proteins and transcription factors,
resulting in extensive population heterogeneity. This Aim will thus carry out deep assessment of proteins relevant
as modified mRNA vaccine targets, and guide antigen design. (3) Transcriptional profiling and microbiome
sequencing for mechanistic investigation. Projects 1-3 and the Clinical Core will generate murine and human
fecal samples associated with successful or unsuccessful responses to C. difficile infection; Core B will quantify
microbiome composition and metatranscriptomic analysis of C. difficile positive samples by RNA-seq. This core
will oversee sequence acquisition and analysis is support of these studies. (4) Data management and archiving.
Core C will work with Core A for standard statistical analysis and will archive and manage the diverse data types
generated by the U19 team.
Terms: <Affect><Antigens><Archives><Bacteriophages><Basal Transcription Factor><Basal transcription factor genes><Bio-Informatics><Bioinformatics><Bovine Species><C diff><C difficile><C. diff><C. difficile><Canine Species><Canis familiaris><Cattle><Cell Body><Cells><Clinical><Clostridioides difficile><Clostridium difficile><Collaborations><Comparative Study><DNA><DNA Alteration><DNA Modification><DNA Modification Process><DNA Sequence Alteration><DNA mutation><Data><Deoxyribonucleic Acid><Dogs><Dogs Mammals><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Diversity><Genetic Variation><Genetic mutation><Genome><Genomics><Human><Hybrids><Immune response><Immunodeficient Mouse><Immunological response><Immunology><Infection><Intestinal><Intestines><Investigation><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Messenger RNA><Methods><Mice><Mice Mammals><Modern Man><Murine><Mus><Outcome><Phages><Population><Population Heterogeneity><Protein Analysis><Proteins><RNA Seq><RNA sequencing><RNA vaccine><RNA-based vaccine><RNAseq><Reporting><Research Resources><Resources><SEQ-AN><Sampling><Sequence Alteration><Sequence Analyses><Sequence Analysis><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Structure><Surface Proteins><System><Transcript Expression Analyses><Transcript Expression Analysis><Transcription Factor Proto-Oncogene><Transcription factor genes><Vaccinated><Vaccines><Variant><Variation><Work><analyze gene expression><archive data><archiving data><bacterial virus><bovid><bovine><bowel><canine><cow><data archive><data archives><data diversity><data management><design><designing><diverse data><diverse populations><domestic dog><fascinate><gene expression analysis><gene expression assay><genomic alteration><heterogeneous population><host response><immune system response><immunogen><immunoresponse><in vivo><interest><mRNA><mRNA vaccine><mRNA-based vaccine><metatranscriptomics><microbiome><microbiome community composition><microbiome composition><microbiome sequencing><microbiome species composition><mobile DNA><model organism><population diversity><protein structure><protein structures><proteins structure><response><statistical analysis><statistics><transcription factor><transcriptional profiling><transcriptome sequencing><transcriptomic sequencing><transposon/insertion element><vaccine candidate><vaccine efficacy>