Key Dates

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

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

PA-20-184 - Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

PA-20-196 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)

Issued by

National Institute of Dental and Craniofacial Research (NIDCR)

Purpose

NIDCR announces its interest in encouraging state-of-the-art, systematic research approaches to determine mechanisms underlying the ability or inability of the immune system to dynamically maintain its functional role against internal and external perturbations, and to examine immune mechanisms of protection against recurrence of chronic inflammation in response to infectious and autoimmune diseases of dental, oral, and craniofacial (DOC) tissues. The expectation is that new knowledge derived from this research will facilitate development of novel, personalized immunomodulatory-based therapies that shift the balance between degenerative and regenerative processes toward protection against episodic recurrence and preventative disease management in a patient-specific manner across the lifespan.

BACKGROUND

The oral mucosal barrier is constantly exposed to a plethora of triggers, including a diverse microbiome, ongoing damage from mastication, and dietary and airborne antigens, all of which require immune control of its barrier function. Recent advances in understanding diseases and conditions involving DOC tissues – periodontitis, peri-implantitis, temporomandibular joint disorders (TMD), oral and oropharyngeal cancers, Sjögren’s Disease, and HIV/AIDS with its associated oral opportunistic infections, among others demonstrate that the immune system significantly contributes to disease onset, progression, and persistence. For example:

• Crosstalk between bone and immune system through the bone marrow niche has been proposed to modulate their respective adaptive functions in the context of inflammatory stimuli and in the context of sequelae in disease pathogenesis.
• Similarities between tumors and the inflammatory wound healing responses are increasingly being recognized. While cancers can be viewed as the consequence of “under-healing”, autoimmune diseases can be considered a consequence of an aberrant “over-healing” with excessive accumulation of extracellular matrix and failure to restore tissue function and architecture.
• Neuronal control of immune cell function and age-related dysfunction in the peripheral systems such as salivary glands, immune modulation of peripheral nociceptors and orofacial pain excitation pathways by inflammatory mediators and immune networks, highlight the role of neuro-immune crosstalk in DOC tissues.
• Emerging evidence indicates that tissue-resident and recruited immune cells interact with stem cell niche in a context-dependent manner and influence their ability to react to stress and form enduring memory. Understanding the crosstalk holds great promise for novel therapies in inflammatory diseases and regenerative medicine.

While progress to date has been encouraging, critical scientific gaps exist regarding our understanding of the relationship between immune system control during maintenance of oral health and disease pathogenesis. Moreover, mechanisms underlying male/female- based, age-related differences in immune reactivity, recurrence-related oral sequelae, oral symptoms presentation and treatment options remain to be understood. Inflammation-driven phenotypic plasticity and its effects on the immune landscape of chronic oral inflammation and tumor development, progression and metastasis are yet to be elucidated. Specifically, how these tissue-specific cues participate in the training of immune responsiveness at the oral site and the mechanisms mediating homeostatic immunity at this interface remain to be defined. Understanding the plasticity of tissue-resident and hematopoietic immune sentinels enriched at the oral mucosal surfaces, and their crosstalk with the microenvironment, will shed light on the mechanisms of persistence and immune memory in the oral cavity. This NOSI will address these gaps by capitalizing on recent discoveries of the immunological basis of DOC diseases and technological progress in the field. For example:

• Recent basic science and clinical research have shown that the innate and adaptive immune systems interact with each other and can regulate gene regulatory networks in a cell-, environment-, and time-dependent manner contributing to robustness of DOC tissues in health and disease. These advances highlight the importance of immunological memory and the interactions between innate and adaptive immunity.
• Clinical successes of cancer immunotherapies created a paradigm of therapeutic manipulation of immunological microenvironment that could potentially be applied to other diseases and conditions, including autoimmune diseases.
• Successful clinical trials using bioelectronic devices stimulating peripheral activity to relieve conditions indicate that it should be possible to modulate chronic inflammatory processes via modulating neural inputs.
• Studies have shown that chronic inflammatory mediators interact with the vasculature and stem cell niche with implications toward development of autotherapies.

These and other critical developments identified a strong need to: 1) advance knowledge of immune training, immune memory and homeostatic immunity of DOC environment, and 2) further develop and adapt novel tools and technologies for precise modulation of immune system plasticity to restore normal homeostasis of DOC tissues. The expectation is that new knowledge derived from this research will facilitate development of novel, personalized immunomodulatory-based DOC therapies that shift a balance between degenerative and regenerative processes toward disease management in a patient-specific manner across lifespan.

Specific Areas of Interest

• Identifying molecular and cellular processes that contribute to tissue-specific immune robustness in DOC tissues
• Deriving approaches and models to target functional plasticity reflecting the health and disease of human DOC environment across lifespan
• Investigating mechanisms of crosstalk of the immune system with other tissues like bone, epithelial, neurological, vascular, lymphatic systems in the context of dysregulated homeostasis of the microenvironment
• Developing clinically-applicable immunomodulatory strategies to maintain health of DOC tissues, and treat or prevent DOC diseases
• Understanding mechanisms of trained immunity that mediate protective immunity against subsequent stress associated with infectious and inflammatory challenges
• Elucidating how microbial- derived metabolites influence oral tissues in the context of chronic inflammation
• Investigating mechanisms of cellular metabolism in immune cells and non-immune cells regulate trained memory and oral immune tolerance
• Interrogating how changes in transcriptional programming and epigenetic rewiring that lead to downstream effects of immune memory at the oral mucosal barrier
• Defining the role of sex differences and age in protection against disease recurrence and development of oral immune tolerance
• Developing and utilizing models of diseases, including animals, ex vivo models (organ cultures, tissue chips), and computational models, to allow examination of molecular and cellular events/processes and to precisely and predictably modulate immune system function

Studies that propose the testing of immune modulators that are already in early or late phases of clinical trials are discouraged unless proposed in the context of studying combination therapies with other novel targeted agents; studies that involve the testing of novel immune modulators are strongly encouraged.

Application and Submission Information

This notice applies to due dates on or after June 5, 2022 and subsequent receipt dates through September 8, 2025. 

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.

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-DE-22-005” (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)

Preethi Chander, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Phone: 301-827-4620
Email: preethi.chander@nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-564-4798
Email: rutbergd@mail.nih.gov