Key Dates

Related Announcements

• May 05, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185.
• May 07, 2020 - NIH Exploratory/Developmental Research Project Grant (Parent R21 Clinical Trial Not Allowed). See NOFO PA-20-195.

Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

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

• Use of mouse lines from the Collaborative Cross (CC) and recombinant inbred intercrosses of CC lines (CC-RIX) to advance understanding of host genetics involved in immune system development, regulation, and function during homeostasis and immune stimulatory conditions;
• Screening of CC mouse lines to identify and characterize new mouse models suitable for specific studies and disease models within the mission of NIAID (i.e., fundamental immunology; asthma or allergic disease; autoimmune disease; primary immune deficiency; cell, tissue or organ transplantation; infectious disease);
• Development of novel CC mouse lines that more closely mimic human genetic variations and immune responses, and validate the genetic factors identified in the CC lines with human samples or human studies.

NIAID has supported these research areas through the expired notice of funding opportunity (NOFO), PAR-18-781 Collaborative Cross (CC) Mouse Model Generation and Discovery of Immunoregulatory Mechanisms (R21 Clinical Trial Not Allowed) and  NOT-AI-21-071 (Using the Collaborative Cross (CC) Mouse Model for Immunoregulatory and Infectious Disease Research). The intent of this NOSI is to indicate continued NIAID interest for research in this area, as described below, through applications to the parent R01 and R21 Notice of Funding Opportunities (NOFOs).

Background

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. This limits the ability to dissect the complex and diverse responses and disease phenotypes observed in humans. Collaborative Cross (CC) mouse lines are designed to overcome these limitations by modeling the 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 14 years, NIAID-funded research, including investigations funded via PAR-18-781 and NOT-AI-21-071, has supported the development and expansion of CC mouse lines and generated a powerful scientific resource. This resource has 1) contributed to our knowledge of immune cell development and distribution within tissues, immune protection, and immune 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 autoantigens; 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-utilized in many research areas, such as the impact of genetics on immune system development, regulation, and function during homeostasis and 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 are not fully utilized for infectious disease research. Current CC lines may not cover all the genomic variations seen in humans and additional lines may be needed for studies of interest to NIAID. The validation of the genetic factors identified in CC lines in human samples is required to increase the significance and reliability of the resource.

Barriers hindering more widespread use of CC mice include insufficient phenotypic characterization of many of the lines for specific studies; costs associated with the initial establishment of colonies; and maintenance of specific CC mouse lines in an investigator's laboratory or institution. This NOSI is developed to address these barriers.

Research Objectives

The purpose of this NOSI is to demonstrate NIAID’s interest in research 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 select and evaluate CC and CC-RIX mouse lines suitable for specific studies and disease models within 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 or protection from: pathogenic infections; vaccines; environmental, food, or drug allergens; autoantigens; or allo- or xeno-antigens.
• Studies of changes in immune regulatory and functional mechanisms across the lifespan.
• Development and characterization of new models for autoimmune diseases, asthma and allergic diseases, allo- or xeno-graft rejection and/or tolerance, or immune responses to infectious diseases that 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.
• Genetic evaluation of Major Histocompatibility Complex-region diversity of CC and CC-RIX mouse lines and its influence on transplant outcomes; characterization of biomarkers that predict allo- or xeno-graft rejection and/or tolerance, including elucidation of molecular mechanisms responsible for biomarker efficacy; and identification of novel immune-altering targets or improvements to existing immunosuppressive therapies that prevent allo- or xeno-graft rejection and/or promote transplant tolerance without compromising protective immunity.
• 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; or
  • 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.

NOTE: Validation of the genetic factors identified in CC lines with human samples or human studies is highly encouraged for all proposed studies.

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 performed in the context of organ or pancreatic islet allo- or xeno-transplantation, vascularized composite allo-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, 2024 and subsequent receipt dates through July 16, 2027.

Submit applications for this initiative using one of the following notice of funding opportunity (NOFO) or any reissues of these announcements 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-24-054” (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.

Inquiries

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

Scientific/Research Contact(s) 

Qian “Joy” Liu, MSc, M.D.
Division of Allergy, Immunology, and Transplantation (DAIT)
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-6621
Email: liujoy@niaid.nih.gov

Kaitlyn Morabito, Ph.D.
Division of Microbiology and Infectious Diseases (DMID)
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-6972
Email: kaitlyn.dambach@nih.gov

Financial/Grants Management Contact(s)

Vandhana Khurana
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2966
Email: khuranav@niaid.nih.gov