Much remains unknown about the genetic and systems-level decision-making that guides innate and adaptive immunity to viruses and bacteria. Without that understanding there are major gaps in strategies to establish and improve vaccines against many NIH Priority Pathogens, and to interpret patterns of human genetic, cellular, and serological variation to predict the efficacy and longevity of immunity in clinical settings and in the field. The Gentics Core will produce an unparalleled resource of mouse mutations for experimental and systems analysis of innate and adaptive immunity. Over the 5 year period of this application, through a combination of forward genetics by ENU mutagenesis and pioneering methods to identify mutations by whole exome sequencing, this Core will generate and identify 210,000 single nucleotide variants that change the protein coding sequence of individual genes in live-breeding C57BL/6 mice. Greater than 80% of all annotated genes will suffer deleterious mutation, and all mutations will be archived in the form of frozen sperm for rapid retrieval. The core will supply homozygous, heterozygous and control mice to all of the Projects of this U19 program and to the broader research community. This Core, in synergy with the other Cores and Projects of this U19 program, will expand the community resource of mouse mutations and datasets that experimentally connect discrete genes with the cells and systems governing innate and adaptive immunity. These resources and datasets will be distributed to the community via repositories and websites to enable researchers to test their own hypotheses about adaptive immunity.
Immunity to viruses and bacteria, especially those representing potential bio-terrorism agents and emerging diseases, depends upon thousands of mostly unexplored genes that come together in sophisticated but poorly understood control systems. This Core will produce a unique and critical experimental resource to define these genes and systems, and thereby open the way for new technologies to promote immunity against these agents.
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