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Issued by

National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

National Center for Complementary and Integrative Health (NCCIH)

National Cancer Institute (NCI)

Purpose

The purpose of this Notice of Special Interest (NOSI) is to inform potential applicants to the National Institutes of Health (NIH) of special interest in research on the etiology and pathogenesis of celiac disease, identification of therapeutic targets, and development of preventative or disease ameliorating therapies/strategies.

Background

Celiac disease is an autoimmune disease that occurs in genetically susceptible individuals who develop an immune response to ingested gluten. This disease affects greater than 1% of the US population, and incidence appears to have been increasing over the last several decades. The only known treatment is life-long strict avoidance of all forms of wheat, rye, and barley. Although a gluten-free diet is an effective treatment in many individuals, recent research has revealed that up to 50% of individuals following a gluten-free diet are inadvertently exposed to gluten, and a substantial minority develop persistent or recurrent symptoms.

Clinical manifestations are multifaceted and include gastrointestinal (ranging from severe malabsorption to subclinical damage of the gastrointestinal tract) as well as extraintestinal (e.g., skin) expressions of disease. Additional manifestations may vary from subclinical damage of the gastrointestinal tract to refractory celiac disease that is non-responsive to a gluten-free diet. Although rare, celiac disease is associated with increased risk of gastrointestinal tract cancers and lymphomas.

The pathogenesis of celiac disease involves a combination of predisposing genes, gluten, and environmental factors. HLA-DQ2 and/or HLA-DQ8 haplotypes are the predominant predisposing genes, and dietary gluten is the major inciting factor in individuals with celiac disease. Numerous other environmental factors influence the development of celiac disease but are less well defined than gluten. The reaction to gluten fragments occurs at the small intestinal epithelium, with both an innate and adaptive immune response. This results in characteristic autoantibodies, histologic changes (intraepithelial lymphocytosis and villous atrophy), and clinical symptoms (e.g., diarrhea or iron deficiency anemia).

While much is understood about the mechanism of disease, unmet needs in understanding celiac disease pathogenesis remain, including limited understanding of pathways of disease and tissue destruction, and what causes the loss of tolerance to a component of food. On March 18-19, 2021, NIAID and NIDDK co-sponsored a virtual workshop that brought together a diverse group of experts in celiac disease and related scientific areas to discuss research focused on celiac disease. The goal of the workshop was to identify research gaps, promote this research area to investigators outside of the field, seek avenues for training new/young investigators on approaches and methods common to the field, and understand the future needs for the most promising research.

Research Objectives

This NOSI encourages, but is not limited to, research applications in the following areas:

Specific Areas of Research Interest to NIAID

• Determining mechanisms underlying loss of oral tolerance
• Identifying triggers of autoimmunity in celiac disease
• Developing strategies to eliminate and revert the pathogenic memory gluten-specific CD4 memory T cells
• Defining the cellular circuits and mechanisms involved in tissue destruction
• Identifying the role of microbiota in the loss of oral tolerance and tissue destruction
• Finding immune modulating interventions and strategies to prevent celiac disease and/or restore tolerance
• Identifying biomarkers to predict tissue destruction in celiac disease
• Determining what makes gluten a harmful dietary antigen that can cause tissue destruction
• Discovering what triggers development of inflammatory T helper-1 responses to a dietary antigen
• Determining how tissue destruction is linked to loss of tolerance
• Identifying pathogenic mechanisms shared between celiac disease and other complex immune disorders
• Developing novel animal models or in vitro models using samples from people with celiac disease that mimic the immunopathology of celiac disease
• Determining the role of gastrointestinal immune response in the development of extra-intestinal complications of celiac

Specific Areas of Research Interest to NCCIH

The National Center for Complementary and Integrative Health (NCCIH) will support research to investigate the mechanisms by which complementary and integrative health approaches prevent gastrointestinal tissue destruction, dysfunctions, autoimmunity, and celiac disease-associated non-gastrointestinal symptoms (e.g., chronic fatigue, migraine, depression and attention-deficit disorder). Complementary and integrative approaches may include natural products (i.e., botanicals, dietary supplements, prebiotics, probiotics, microbial therapeutics) or mind/brain-focused practices (i.e., meditation, hypnosis), body-based approaches (i.e., acupuncture, massage, spinal manipulation), meditative exercise (i.e., yoga, tai chi, qi gong), in isolation or in combination with gluten-free therapies. NOTE: NCCIH only accepts mechanistic clinical trials (NOT-AT-20-001) and will not accept a clinical trial that measures the efficacy or effectiveness of any intervention through these FOAs.

Specific Areas of Research Interest to NCI

For cancer or tumor-associated celiac disease, study questions may include, but are not limited to:

• Determining molecular or cellular immune mechanisms and responses underlying tumor associated celiac disease
• Determining the role of gastrointestinal inflammation in the development of GI or extra-intestinal cancers that are sequela of celiac disease
• Elucidating mechanisms whereby commensal or pathogenic organisms, such as enteric microbiome, promote or exacerbate celiac disease GI inflammation, leading to cancer
• Identifying or characterizing rare cases of immune-checkpoint blockade induced celiac disease
• Conducting translational preclinical research and clinical trials of microbiota, natural product, or nutrition and diet interventions to treat and/or prevent celiac disease development for improving cancer therapeutic outcome.

Specific Areas of Research Interest to NIAMS

The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) mission is to support research into the causes, treatment, and prevention of arthritic, rheumatic, musculoskeletal, and skin diseases. In the context of this NOSI, NIAMS is interested in research related to the symptoms, co-morbidities, and complications of celiac disease focused in NIAMS mission areas (including but not limited to skin conditions, osteoporosis/osteopenia, arthritis, joint inflammation) and the impact of pathways disrupted by celiac disease (e.g., tissue cross-talk, gut microbiome imbalance, etc.) in the development and progression of diseases within the NIAMS mission.

IC-Specific Application and Submission Information:

Applicants must select the IC and associated FOA to use for submission of an application in response to the NOSI. The selection must align with the IC requirements listed in order to be considered responsive to that FOA. Non-responsive applications will be withdrawn from consideration for this initiative. In addition, applicants using NIH Parent Announcements (listed below) will be assigned to those ICs on this NOSI that have indicated those FOAs are acceptable and based on usual application-IC assignment practices.

This notice applies to due dates on or after January 12, 2022 and subsequent receipt dates through January 7, 2025.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) listed above for NIH Institutes participating in this NOSI, or any reissues of these announcements through the expiration date of this notice.
 

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-22-004" (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

Scientific/Research Contact(s)

Annette L. Rothermel, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3477
Email: arothermel@niaid.nih.gov

Hye-Sook Kim, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-827-6910
Email: hye-sook.kim@nih.gov

Katarzyna (Kasia) Bourcier, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute (NCI)
Telephone: 240-276-7515
Email: bourcierkd@mail.nih.gov

Lillian S. Kuo, Ph.D.
Division of Cancer Biology
National Cancer Institute (NCI)
Telephone: 240-276-7687
Email: lillian.kuo@nih.gov

Marie Mancini, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5032
Email: mancinim2@mail.nih.gov

Financial/Grants Management Contact(s)

Tamia Powell
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2982
Email: tamia.powell@nih.gov

Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: CarowS@MAIL.NIH.GOV

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: wolfreyc@mail.nih.gov

Sahar Rais-Danai
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-496-1472
Email: Sahar.Rais-danai@nih.gov