November 3, 2022
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)
National Institute on Drug Abuse (NIDA)
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.
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.
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:
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.
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Sam Ananthan, Ph.D.
National Institute on Drug Abuse (NIDA)