Notice Number: NOT-AI-19-040

Key Dates
Release Date : February 07, 2019

PA-18-591

Issued by
National Institute of Allergy and Infectious Diseases (NIAID)
Division of Program Coordination, Planning and Strategic Initiatives, Office of Research Infrastructure Programs (ORIP )

Purpose

Humanized immune system (HIS) mice are severely immune deficient mice that are engrafted with human immune cells or tissues, such that the immune system of the mouse is partially to primarily replaced with human immune cells and tissues. The first HIS mouse models were developed in 1988 using a single immunodeficient mouse strain and several different sources of human hematopoietic stem cells. Currently, eight humanized mouse strains constitute the major platforms used to generate HIS mice using a variety of fetal and non-fetal derived human immune cells and tissues. Major scientific advances have been made in understanding infectious disease pathogenesis and development of therapeutics using HIS mouse models made with human fetal tissues.

While no single HIS model is universally appropriate or optimal for all applications, various models can recapitulate key aspects of human T cell immunity but are less able to recapitulate human innate immunity and antibody responses, regardless of the human tissue source. In addition, few direct comparisons have been conducted of HIS mice derived using fetal vs. non-fetal human tissue sources (https://www.niaid.nih.gov/research/humanized-mouse-model-workshop).

The National Institute of Allergy and Infectious Diseases (NIAID) and the Office of Research Infrastructure Programs (ORIP) announce the opportunity for investigators with relevant active research project grants and cooperative agreements to submit administrative supplements according to PA-18-591, Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional), for funded projects that could conduct detailed characterization, direct comparisons and further development of HIS mouse models, with a particular interest in models that use non-fetal sources of human cells/tissue (e.g., cord blood, neonatal, adult) for immune reconstitution. Direct comparisons to models derived from human fetal tissue are encouraged in all areas outlined below.

Institute, Center (IC) and Office-specific Interests

National Institute of Allergy and Infectious Diseases (NIAID):

NIAID's interests include, but are not limited to:

• Detailed immunologic characterization and/or optimization of HIS mouse models reconstituted with non-fetal sources of human cells/tissues that closely reflect/demonstrate human T cell immune responses, including functional analysis of various immune subsets.
• Development or optimization of HIS mouse models:

• that can recapitulate human innate immunity or B cell/antibody responses, in terms of both subset development and function
• to characterize host immune responses to infectious pathogens or during the development and progression of immune-mediated diseases
• to study infectious disease pathogenesis or transmission of pathogens that infect or manipulate immune cells as part of their lifecycle/replication process
• that would facilitate therapeutic discovery, target identification, determination of mechanism of action, or preclinical candidate therapeutic evaluation/development

• Characterization and development of mucosal immune responses in HIS mice generated with non-fetal human tissue.
• Development of secondary lymphoid tissues following engraftment.
• Development of HIS mice that support HIV-1 infection or HIV-1 co-infections with Mycobacterium tuberculosis or hepatitis B and C viruses either systemically or mucosally and do not result in the development of graft-versus-host disease. NOTE: The proposed humanized mouse models need to support the development of HIV therapeutics, HIV cure strategies, or HIV prophylaxis (vaccines and chemical pre-exposure prophylaxis).
  

Office of Research Infrastructure Programs (ORIP)

ORIP is interested in research focused on:

• Approaches to generate new/improved HIS mice model resources reconstituted with non-fetal sources of human cells/tissues for AIDS research using repopulation of associated lymphoid tissues and stromal niches of the mouse GI tract, CNS and female reproductive tract to study virus transmission, HIV prevention or persistence.
• Developing approaches for building robust components of the human immune system in HIS mice using human-derived iPSCs with or without combination with other non-fetal sources of human cells/tissues for the purposes of disease-modeling and regenerative medicine.
• Studies of the use of the non-fetal sources of HSC for the early mouse embryonic reconstitution to enable human hematopoietic maturation during the normal development.
• Developing effective reprogramming and trans differentiation approaches for generation of transplantable components of the immune system from human adult cells and tissues for effective reconstitution in HIS mice.
  

Budget:

To be eligible, the parent award must be able to receive funds in FY19 (Oct. 1, 2018-Sept. 30, 2019) and is not in an extension period.

Supplement budget requests cannot exceed $250,000 in direct costs exclusive of Facilities and Administrative costs on sub-awards, OR the direct costs of the current parent award, whichever is less. Requests must reflect the actual needs of the proposed project. Requests are for one year of support only. Modular and categorical budgets are permitted.

The earliest anticipated start date is August 1, 2019.

Eligible Individuals (Program Director/Principal Investigator)

Individual(s) must hold an active grant or cooperative agreement. For supplements to parent awards that include multiple PDs/PIs, the supplement may be requested by any or all of the PDs/PIs (in accordance with the existing leadership plan) and submitted by the awardee institution of the parent award.

Submitting Applications:

Supplements to Grants/Cooperative Agreements:

For administrative supplement to grants and cooperative agreements, supplement requests must be submitted in accordance with the parent program announcement: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) PA-18-591.

Applicants should begin the supplement application abstract by stating “This application is being submitted in response to NOT-AI-19-040”

Page Limits: The Research Strategy should be approximately 5 pages, not including the abstract.

Supplement requests should be submitted electronically if allowed by the parent mechanism. Applicants are strongly encouraged to notify the program contact at the Institute supporting the parent award that a request has been submitted in response to this FOA in order to facilitate efficient processing of the request.

Due Date:

All requests, regardless of the parent award funding mechanism, must be received by 5:00 PM Pacific Daylight Time (P.D.T.) on May 1, 2019 for funding in FY 2019.

Scientific Review Process:

Each IC will conduct administrative reviews of applications submitted to their IC separately, and will support the most meritorious applications submitted for consideration, based upon availability of funds.

Criteria:

1. Is the work proposed within the scope of the active award?
2. Does the work proposed address one of the components listed under the IC-specific research objectives?
3. Does the work proposed have scientific merit?
4. Is the work likely to stimulate additional activity leading to progress on HIS mouse model development?

Inquiries

Please direct all inquiries to:

Mercy PrabhuDas, PhD
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases (NIAID )
Telephone: 240-627-3534
Email: [email protected]

Brigitte Sanders, DVM, PhD
Division of AIDS
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3209
Email: [email protected]

Michael Schaefer, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3364
Email: [email protected]

Oleg Mirochnitchenko, PhD
Office of Research Infrastructure Programs
Telephone: 301-435-0748
Email: [email protected]