NIH – Collaborative Cross (CC) Mouse Model Generation and Discovery of Immunoregulatory Mechanisms (R21 Clinical Trial Not Allowed)

May 21, 2018 by School of Medicine Webmaster

The goal of this FOA is to support the use of Collaborative Cross (CC) mouse lines to advance understanding of the host genetics involved in immune regulation and function and to further exploit CC mouse lines that more faithfully reflect human immune responses.  The basis of this research program is to identify previously unappreciated key immune regulatory genes, signaling pathways, or mechanisms; to map the underlying genetic basis for immune responses triggered by pathogens, commensals, vaccines or adjuvants; to identify host susceptibility factors and mechanisms of pathogen-induced immunopathology; or to determine the immune genes and pathways contributing to the development and progression of immune-mediated diseases, such as allergy/asthma, autoimmunity, primary immunodeficiency, inflammation, and cell/organ/tissue transplant rejection or tolerance.


The use of mice as model organisms for immunology research has led to significant advances in our understanding of the mechanisms governing human immune activation and regulation, as well as dysregulation.  To date, most mice used in laboratory studies represent inbred strains with limited genetic diversity, which greatly facilitates the manipulation of host genome to answer mechanistic questions.  However, this approach limits the ability to dissect complex and diverse responses observed in humans because of the limited genetic diversity intrinsic to inbred mice.  The CC mouse lines are designed to overcome these limitations by modeling the genetic diversity found in the human population in a controlled and reproducible manner.

The CC is a panel of recombinant-inbred (RI) lines derived from initially randomized crosses of eight genetically-diverse founder mouse strains which include three wild-derived strains.  Existing CC mouse lines contain high levels of genetic variation, capturing more than 90% of the known genetic variations present in the genomes of laboratory mice, with the presence of more than 45 million single nucleotide polymorphisms (SNPs) and more than 4 million indels (nucleotide insertions or deletions) uniformly distributed across the entire genome.  Significant efforts have been made to characterize the genomes of the CC mice over the years.  The CC genome data, including the initial haplotype reconstructions and recent whole genome sequencing of 69 CC lines, is publicly available.  The CC provides a valuable translational tool to facilitate discovery of genetic factors associated with complex diseases with high resolution and supports genome-wide network analysis. RI lines are independently derived and yet genetically related.  More importantly, like other inbred strains, RI lines represent an infinitely reproducible population of genetic clones, which allows for repeated measurements over time and comparative studies across different laboratories.  In order to extend the mapping power and overcome the genome incompatibilities within the inbred CC lines, recombinant inbred intercrosses of CC lines (CC-RIX) also have been generated.  The CC-RIX mice display additional unique genotypes, extend the phenotypic diversity CC mouse lines, and facilitate studies of epigenetic effects.

The CC resource has a proven track record of creating new, highly useful animal models for the discovery of genes in immune protection and immune regulation.  NIAID has funded the use and further development of the CC mouse lines for immunology and infectious disease research since 2009 as part of its solicited research programs including the Systems Approach to Immunity and Inflammation Program and the Regional Centers of Excellence for Biodefense and Emerging Infectious Diseases Research (RCE) Program, as well as through the support of investigator-initiated research projects.  The majority of NIAID-funded research incorporating the CC mouse models has addressed the impact of host genetic variation on immunity to emerging viral pathogens, including Norovirus, severe acute respiratory coronavirus (SARS-CoV), Ebola, West Nile Virus, Dengue virus, Zika virus, Hepatitis C virus), human Herpesvirus-8 (HHV-8), Influenza, and Chikungunya.  Investigators have also used the CC in studies of other infectious pathogens, such as Mycobacterium tuberculosisNeisseria sp., Toxoplasma gondii, and nematode (Onchocerca volvulus).  These studies have contributed significantly to our knowledge of the pathogenesis of infectious diseases.

Despite the enormous potential of the CC mice, the resource is underutilized within the immunology research community, especially in research areas of immune system development and regulation, asthma/allergy, autoimmunity, primary immunodeficiency, inflammation, and cell/organ/tissue transplant rejection or tolerance. While genome information is available for CC mouse lines, insufficient phenotypic characterization of many of these lines poses a significant barrier to use, especially for investigators not currently working with the CC mice.  Additional barriers include the costs associated with initial characterization and maintenance of specific CC mouse lines in an investigator’s laboratory/institution.  This FOA will help address these hurdles to broader utilization of this valuable resource by the immunology research community.  The overarching goal of this FOA is to advance our understanding of the host genetics involved in immune regulation/function and to support further development of CC mouse lines that more faithfully reproduce human immune responses.

Research Objectives and Scope

This FOA will support the further development and use of CC, CC derivatives with reproducible genomes and CC-RIX mice for immunologic investigation in areas of interest to NIAID.  These research areas include, but are not limited to:

  • Studies of immune system development, regulation, and function during homeostasis and in response to vaccine adjuvants and/or antigenic challenge (e.g. infectious pathogens, vaccines, model antigens)
  • Identification of novel immune regulatory genes and their mechanisms of action
  • Development, generation, and maintenance of innate and adaptive immunity during homeostasis or in response to infections or vaccinations at all stages of life, starting with in utero development and including early life through aging
  • Characterization of host genetics, microbial flora, and immune regulatory outcomes across the lifespan
  • Studies of regulatory mechanisms of environmental exposure and risk factors that promote atopic or asthma diathesis
  • Development and characterization of new models for asthma and allergic disease phenotypes and endotypes
  • Identification of genetic determinants underlying the differences in sensitivity to allergens, and response to allergen‐specific immunotherapy
  • Identification of genetic contributions to routes of allergic sensitization
  • Development and characterization of new models for autoimmune diseases
  • Identification of genetic and immune system contribution to autoimmune diseases
  • Characterization of the genetic basis of primary immunodeficiency diseases
  • Development and characterization of new models for cell/organ/tissue rejection or tolerance
  • Studies of immune system development, regulation, and function in response to alloantigens
  • Studies of infectious disease pathogenesis with the ultimate goal of identifying:
  • Novel targets/antigens for vaccine development
  • Novel targets for therapeutics development
  • Infectious disease-related biomarkers, including:
    • Biomarkers to predict susceptibility to infection and/or diagnose an infectious disease;
    • Biomarkers to diagnose individuals infected with pathogens or who have been exposed to toxins;
    • Biomarkers to predict or monitor a subject’s response to therapeutics or vaccinations;
    • Biomarkers from natural history studies that could be used to assess disease progression in acute and chronic infectious diseases.

Research areas NOT appropriate for this FOA include:

  • Studies of immune mechanisms related to cancer development and treatment, including anti-tumor responses in hematopoietic stem cell or bone marrow transplantation
  • Studies of immune mechanisms of HIV infection and treatment
  • Studies of hematopoietic stem cell or bone marrow transplantation, including graft versus host disease, unless in the context of organ or pancreatic islet transplantation, or studies of hematopoietic stem cell transplantation for autoimmune diseases
  • Studies utilizing other diverse mouse strains, without inclusion of the CC and CC-RIX mouse resource
  • Analysis of genes, pathways, or regulatory mechanisms of immunity using only in vitro systems (e.g. in the absence of in vivo mouse studies)
  • Clinical trials, though the use of human samples to validate findings in the CC and CC-RIX mice is allowed

Clinical research using human samples to validate findings in the CC mice are strongly encouraged.  Applicants will have the liberty of choosing specific CC mouse lines to be analyzed, and the pipeline used to phenotype the mice. Investigators may utilize a broad array of technologies for the characterization of these mice, including but not limited to, antibody titers, measurement of antigen-specific immune cells, secretion profiles of cytokines and other soluble factors, tissue immunohistochemistry, clinical scores, and pathogen burden/load.

Deadlines:  September 4, 2018, September 3, 2019, and September 9, 2020.  The announcement gives a single deadline for letters of intent (August 4, 2019), but this probably is incorrect; check with the FOA contacts if interested in applying in 2019 or 2020.


Filed Under: Funding Opportunities