Notice of Special Interest (NOSI): Defining Mechanisms of Disease Recurrence in Dental, Oral, and Craniofacial Tissues

Notice Number: NOT-DE-20-001

Key Dates
Release Date: February 18, 2020
First Available Due Date: June 05, 2020
Expiration Date: May 08, 2022

Related Announcements

PAR-19-172 Achieving Tissue Robustness Through Harnessing Immune System Plasticity (R01 Clinical Trial Not Allowed)
PAR-19-173 Achieving Tissue Robustness Through Harnessing Immune System Plasticity (R21 Clinical Trial Not Allowed)

Issued by
National Institute of Dental and Craniofacial Research (NIDCR)


NIDCR announces its interest in encouraging studies that examine immune mechanisms of protection against recurrence of inflammation in response to infectious and autoimmune diseases of dental, oral, and craniofacial (DOC) tissues, and to develop immunomodulatory approaches to protect against episodic recurrence.


Episodic recurrence of inflammation in response to infections or autoimmune conditions has been a long-standing issue in recalcitrant disease manifestations of DOC tissues. Conditions with recurrence are characterized by patterns of exacerbation and quiescent periods. The oral cavity is one of the sites of early manifestation of recurrent systemic diseases and these diseases in turn lead to poor oral health. Due to their poorly understood etiology and resultant challenge for medical treatment and patient management, recurrent diseases attract much attention. For example, in case of autoimmune oral lichen planus (OLP), oral lesions are known to recur more persistently compared to skin manifestations. Sex differences in recurrence-related sequelae have also been described. In women, OLP lesions are more likely to develop into oral leukoplakia, and patients with oral leukoplakia are at increased risk of oral squamous cell carcinoma. Advances in treatment management of recurrent conditions have led to further questions on the underlying mechanisms of observed outcomes. In HIV-infected patients with low CD4 counts, significantly lower number of episodes of oropharyngeal candidiasis and other invasive fungal infections were observed with continuous fluconazole therapy, compared with episodic fluconazole treatment for recurrences. GWAS analysis of recurrent aphthous stomatitis have identified associations at immune regulatory loci in the etiology of mouth ulcers. Additionally, recent mechanistic studies on the immunology front have shown that the epigenetic signature of LPS-induced tolerance is reversed upon ‘training’ with b-glucan; implying a role for immune memory in innate immunity and has come to be termed as “trained memory”. This “training” has been shown to reinstate proper cytokine responses of human macrophages after LPS-induced immunological tolerance.

Immune memory, the ability to remember and respond more robustly against a second encounter, is maintained by distinct populations of long-lived memory cells that can persist without residual antigen. Traditionally, this memory has been attributed to the adaptive arm of immunity. The concept of “trained immunity” refers to an enhanced state of immunity to a future inflammatory or microbial challenge that is based on innate immune memory. Recently, this kind of immune memory has been described in organisms lacking T and B cells and in myeloid cells. Induction of trained memory appears to be mediated by long-term adaptations that persist over time despite the loss/cessation of the inductive stimulus.

Changes in immune and neuroendocrine signaling, metabolic pathways coupled with changes in transcriptional regulation of epigenetic modifications may be explained by some of the long-term rewiring of the trained memory. Understanding the mechanisms of trained immunity that mediate protective immunity against subsequent stress associated with infectious and inflammatory challenges are essential to immune robustness in health and in disease and immunomodulatory therapies for preventing/tolerating recurrence of such diseases of the oral cavity. New opportunities to probe these knowledge gaps are now possible by recent advances in various fields, including immune engineering, immunometabolism, and immune memory and tissue-resident immunity.

This area of interest is aligned with NIDCR’s interest in immune robustness of DOC tissues. This topic folds into NIDCR’s greater interests expressed in PAR 19-172, -173 on Achieving Tissue Robustness Through Harnessing Immune System Plasticity.


Areas of interest include, but are not limited to:

  • Investigating the role of cross talk between oral tissues and systemic health in mediating tissue-resident immunity.
  • Elucidating how cellular metabolism in immune cells and non-immune cells regulate trained memory.
  • 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.
  • 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 involved in protective immunity against recurrence.

Applications for this Notice must submit an application through the FOAs PAR-19-172, PAR-19-173 titled Achieving Tissue Robustness Through Harnessing Immune System Plasticity (R01 Clinical Trial Not Allowed) and Achieving Tissue Robustness Through Harnessing Immune System Plasticity (R21 Clinical Trial Not Allowed).

Application and Submission Information

This notice applies to due dates on or after June 5, 2020 and subsequent receipt dates through September 8, 2022.

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.

  • PAR-19-172 - Achieving Tissue Robustness Through Harnessing Immune System Plasticity (R01 Clinical Trial Not Allowed)
  • PAR-19-173 Achieving Tissue Robustness Through Harnessing Immune System Plasticity (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-DE-20-001” (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 be not be considered for the NOSI initiative.



Please direct all inquiries to:

Please direct all inquiries to the Scientific/Research, Peer Review, and Financial/Grants Management contacts in Section VII of the listed funding opportunity announcements.