Notice of Special Interest (NOSI): Using the Collaborative Cross (CC) Mouse Model for Immunoregulatory and Infectious Disease Research
Notice Number:

Key Dates

Release Date:

July 30, 2021

First Available Due Date:
October 05, 2021
Expiration Date:
September 08, 2024

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
PA-20-195 - NIH Exploratory/Developmental Research Project Grant (Parent R21 Clinical Trial Not Allowed)

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)


The National Institute of Allergy and Immunology (NIAID) is issuing this Notice of Special Interest (NOSI) to highlight interest in receiving grant applications focusing on the following area(s):

  • Use mouse lines from the Collaborative Cross (CC) and recombinant inbred intercrosses of CC lines (CC-RIX) to more faithfully reproduce human immune responses and to advance understanding of the host genetics involved in immune regulation and function
  • Screen CC mouse lines to identify and characterize lines suitable for specific studies and disease models within the mission of NIAID (e.g., fundamental immunology, immune-mediated diseases, infectious diseases).


Human genetic variations contribute to heterogeneity in immunity and disease susceptibility. Although 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, most mice used in laboratory studies are inbred strains with highly restricted genetic diversity, which limits our ability to dissect complex and diverse responses observed in humans. CC mouse lines are designed to overcome these limitations as they can model genetic diversity found in humans.

The CC is a collection of recombinant-inbred (RI) mouse lines derived from initially randomized crosses of eight genetically diverse founder mouse strains that included 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. They represent a fully reproducible population of genetic clones, which allows for repeated measurements over time and comparative studies across different laboratories. In addition, to extend the mapping power and to overcome the genome incompatibilities within the inbred CC lines, recombinant inbred intercrosses of CC lines (CC-RIX) have been generated. These lines have extended the phenotypic diversity of CC mouse lines and facilitated studies of epigenetic effects.

Over the last 10 years, NIAID-funded research, including investigations funded via PAR-18-781, has supported development and expansion of CC mouse lines and provided a powerful scientific resource. This resource has 1) contributed to our knowledge of immune protection and regulation; 2) enabled the discovery of new genes and immunoregulatory mechanisms; 3) allowed for examination of the impact of host genetic variation on immunity to emerging viral pathogens; and 4) advanced understanding of pathogenesis of numerous infectious diseases.

Despite scientific advances attributed to the use of CC mouse lines, this resource continues to be under-used in many research areas, such as the impact of genetics on immune system development, regulation, and function across the lifespan, and the mode of action of the genetic factors in allergic diseases, autoimmune diseases, inflammation, or cell/organ/tissue rejection or tolerance. In addition, CC mouse lines have not been fully utilized for infectious disease research.

Barriers hindering their more widespread use include insufficient phenotypic characterization of many of these lines for specific studies and the costs associated with initial establishment of colonies and maintenance of specific CC mouse lines in an investigator's laboratory/institution. The overarching goal of this NOSI is to continue validating the utility of CC mouse lines to 1) more faithfully reproduce human immune responses and advance our understanding of the host genetics involved in immune regulation/function and 2) to screen CC lines to identify and characterize lines suitable for specific studies and disease models within NIAID’s mission.

This NOSI is a furtherance of the previously expired PAR-18-781 Collaborative Cross (CC) Mouse Model Generation and Discovery of Immunoregulatory Mechanisms (R21 Clinical Trial Not Allowed).

Research Objectives

The purpose of this NOSI is to evaluate the utility of CC and CC-RIX mouse lines for research areas of interest to NIAID. These research areas include, but are not limited to:

  • Studies of immune system development, regulation, and function during homeostasis or in response to infections, vaccinations, or alloantigens across the lifespan.
  • Studies of regulatory mechanisms of environmental exposure and risk factors that promote atopic or asthma diathesis, or autoimmunity.
  • Development and characterization of new models for autoimmune diseases, asthma and allergic diseases, allograft rejection and/or tolerance designed to better-predict the human clinical experience.
  • Identification of genetic determinants underlying autoimmune diseases, primary immunodeficiency diseases, routes of allergic sensitization, differences in sensitivity to allergens, and response to allergen‐specific immunotherapy.
  • Characterization of biomarkers for prediction of allograft rejection and/or tolerance, and identification of novel targets for immunosuppressive or immune-altering drugs with the goal of effectively preventing allograft rejection and/or promoting tolerance without compromising protective immunity, or otherwise improving-upon current non-specific immunosuppressive therapies used in transplantation.
  • Studies of infectious disease pathogenesis with the goal of identifying:
    • Novel targets/antigens for vaccine development and therapeutics development
    • Novel animal models for infectious disease research
    • Infectious disease-related biomarkers for predicting susceptibility to infection or infectious diseases and response to therapeutics or vaccinations, diagnosis of individuals infected with pathogens or exposed to toxins, and assessment of disease progression in acute and chronic infectious diseases

This NOSI will not consider the following research areas:

  • Studies of immune mechanisms related to cancer development and treatment or 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 mouse strains other than the CC and CC-RIX mouse resources.
  • Studies only using in vitro systems with cells from CC or CC-RIX mice.
  • Clinical trials.

Application and Submission Information

This notice applies to due dates on or after October 5, 2021 and subsequent receipt dates through September 7, 2024.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

  • PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-20-195 – NIH Exploratory/Developmental Research Project Grant (Parent R21 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-AI-21-071” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.


Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Qian “Joy” Liu, M.D., M.Sc.
Division of Allergy, Immunology and Transplantation (DAIT)
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-6621

Michael R. Schaefer, Ph.D.
Division of Microbiology and Infectious Diseases (DMID)
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3364

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