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-20-200 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)

PA-20-188 - NIH Pathway to Independence Award (Parent K99/R00 Independent Clinical Trial Not Allowed)

PA-20-190 - Mentored Research Scientist Development Award (Parent K01 - Independent Clinical Trial Not Allowed)

PAR-21-208 - Cutting-Edge Basic Research Awards (CEBRA) (R21 Clinical Trial Optional)

PA-21-049 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship for Students at Institutions with NIH-Funded Institutional Predoctoral Dual-Degree Training Programs (Parent F30)

PA-21-050 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship for Students at Institutions Without NIH-Funded Institutional Predoctoral Dual-Degree Training Programs (Parent F30)

PA-21-051 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (Parent F31)

PA-21-052 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research (Parent F31-Diversity)

PA-21-048 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship (Parent F32)

Issued by

National Institute on Drug Abuse (NIDA)

Purpose

The National Institute on Drug Abuse (NIDA) is issuing this Notice of Special Interest (NOSI) to inform applicants about NIDA's special interest in innovative research that uses chemical and pharmacological approaches to identify and target epigenetic regulators and mechanisms for the treatment of addiction and substance use disorders.

Background

Epigenetic modifications induced by addictive drugs have been implicated in mediating enduring changes in brain function that drive drug-seeking and relapse. Specific epigenetic changes induced by addictive substances such as cocaine, amphetamine, methamphetamine, morphine, heroin, nicotine, cannabis, and inhalants have been identified that include DNA methylation and several forms of histone modifications such as methylation, acetylation, phosphorylation, adenylation, and ubiquitination. Additionally, recent evidence suggests that monoaminylation of histone H3 glutamine by dopamine in the ventral tegmental area (VTA) contributes to cocaine- and heroin-seeking behavior following abstinence. Pharmacological manipulation of epigenetic-related proteins is sufficient to ameliorate drug-induced behavioral, transcriptional, and physiological changes in animal models. For example, inhibition of histone deacetylases, inhibition of bromodomain and extra terminal domain (BET) histone acetylation reader proteins such as BRD4, as well as pharmacological manipulation of other DNA- and histone-modifying enzymes such as, DNMT, KDM6b, G9a, and PRMT1, attenuate behavioral changes induced by addictive substances. Targeting the epigenetic alterations induced by addictive substances has emerged as a potentially promising avenue for the development of novel anti-addiction therapies.

Significant progress has been made in delineating the structural and functional basis by which histone and DNA-modifying enzymes bring about pathophysiological changes. These developments have ushered in a new era in epigenetic drug discovery by targeting the enzymes and multiprotein enzyme complexes that function as readers, writers, and erasers of epigenetic marks. Recent advances in the application of virtual and focused-library screening, structure-based drug design, and application of targeted protein degradation approaches have accelerated the identification and optimization of small molecule modulators of epigenetic targets with isoform/domain selectivity and brain penetration capacity, thus enhancing the potential for clinical translation. These developments make it timely to explore the potential of targeting epigenetic regulators for addressing addiction and substance use disorders. This initiative, therefore, is aimed at expanding the repertoire of compounds that can be used as pharmacological tools to gain a better understanding of the molecular mechanisms underlying epigenetic alterations induced by addictive substances and for exploring promising ligands as potential therapeutic agents for the treatment of substance use disorders.

Research Objectives

The goal of this announcement is to encourage basic preclinical research aimed at identifying and targeting specific enzymes and pathways that play a key role in epigenetic changes induced by addictive drugs with the goal of developing pharmacological tools, methods, and therapeutic interventions for the treatment of substance use disorders and addiction. Examples of research areas of interest in the context of epigenetic drug discovery for substance use disorders include, but are not limited to:

• Identification of epigenetic targets and pathways amenable for modulation by small molecules
• Screening of large or focused libraries of compounds to identify compounds for use as pharmacological tools and as leads for drug development
• Application of structure-based virtual screening and related computational approaches to identify novel lead compounds
• Application of biophysical methods including structure-determination using cryo-EM, X-ray, NMR, etc., to aid lead discovery and to gain insights into the mechanism of action
• Use of artificial intelligence and machine learning approaches to aid epigenetic target discovery as well as to identify drugs that can be repurposed
• Application of rational medicinal chemistry approaches to optimize lead compounds to improve potency and selectivity and to mitigate side effects
• Investigation of drug design and drug delivery approaches to improve physicochemical and pharmacokinetic properties including brain penetration
• Application of rational design approaches to generate PET ligands and fluorescent probes to aid in visualizing and understanding epigenetic reader/writer dynamics in human brain
• Pharmacological studies using tool compounds to gain mechanistic insights into how epigenetic changes induced by addictive substances influence behavioral changes
• Pharmacological studies with lead compounds to establish efficacy, safety, and tolerability
• Identification of downstream targets of epigenetic changes induced by addictive substances

Application and Submission Information

This notice applies to due dates on or after February 5, 2023 and subsequent receipt dates through January 8, 2026. 

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) 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 Grant Program (Parent R21 Clinical Trial Not Allowed)
• PA-20-200 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)
• PA-20-188 - NIH Pathway to Independence Award (Parent K99/R00 Independent Clinical Trial Not Allowed)
• PA-20-190 - Mentored Research Scientist Development Award (Parent K01 - Independent Clinical Trial Not Allowed)
• PAR-21-208 - Cutting-Edge Basic Research Awards (CEBRA) (R21 Clinical Trial Optional)
• PA-21-049 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship for Students at Institutions with NIH-Funded Institutional Predoctoral Dual-Degree Training Programs (Parent F30)
• PA-21-050 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship for Students at Institutions Without NIH-Funded Institutional Predoctoral Dual-Degree Training Programs (Parent F30)
• PA-21-051 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (Parent F31)
• PA-21-052 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research (Parent F31-Diversity)
• PA-21-048 - Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship (Parent F32)

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-DA-24-004” (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)

Sam Ananthan, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-2199
Email: sam.ananthan@nih.gov