April 11, 2023
PA-20-200 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)
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-20-190 - Mentored Research Scientist Development Award (Parent K01 - Independent Clinical Trial Not Allowed)
PA-20-208 - Substance Use/Substance Use Disorder Dissertation Research Award (R36 - Clinical Trials Optional)
PAR-21-208 - Cutting-Edge Basic Research Awards (CEBRA) (R21 Clinical Trial Optional)
National Institute on Drug Abuse (NIDA)
This Notice of Special Interest (NOSI) encourages innovative studies on the role of organelle interactions and communications, and how organelle dynamics affect cellular homeostasis in the context of addiction.
Organelles are dynamic structures that exhibit intercommunication in the regulation of critical cellular functions including metabolism, signaling, structural integrity, and apoptosis. Physical interactions between membrane organelles are critical to key physiological processes, as disruption of effective organelle intercommunication can trigger cascades of events leading to pathogenic outcomes. Addictive drugs can interfere with organelle communication and function via their effects on diverse cellular activities, such as altered endosomal trafficking and recycling, initiation of ER stress, mitochondrial dysfunction, and autophagy. Addictive substances can also affect many aspects of CNS cellular functions, such as proliferation, chemotaxis, phagocytosis, as well as the synthesis, secretion, transport, and degradation of proteins; organelle dynamics are critical components of these effects.
Increasing evidence indicates that the subcellular location of a receptor matters for drug effects. For example, several studies suggest that G-protein-coupled receptor (GPCR) signaling from intracellular compartments can play important roles in cellular responses to drugs. There are now distinct ligand-activated signaling differences identified for plasma membrane-localized and intracellular populations of the same receptor.
Novel imaging studies and protein interaction profiles have revealed that activation of intracellular receptors play significant roles in cell signaling. For example, activation of intracellular receptors has been shown to promote structural neuroplasticity, and groundbreaking studies of protein trafficking patterns have advanced our understanding of opioid tolerance at the organelle level. How organelle intercommunication is mechanistically linked to addiction-related receptor signaling and trafficking patterns, and how that further mediates features of neuronal circuitry and ultimately, behavior, is understudied.
A quantitative network of organelle interactions and protein dynamics is needed to improve our mechanistic understanding of the cell biology of addictive drug effects. Recently developed powerful imaging tools and robust intracellular assays offer the opportunity to construct an organelle interactome. This will advance the research field to understand inter-organelle communication pathways and organelle dynamics and the impact of addictive drugs on these processes. Constructing in-depth analyses of addictive drug impacts on organelle dynamics may lead to a novel target space for the development of future therapeutics in substance use disorders.
Characterize organelles and molecules involved in protein trafficking. How elements of clustering protein complexes, such as endocytic adaptor proteins and GPCR binding proteins, as well as internalization patterns and trafficking routes may be changed subsequent to substance use.
Identify and characterize functional crosstalk between organelles in the context of addiction. How addictive drugs disrupt organelle communications and cellular processes. Comprehensive signaling network and brain circuit plasticity analyses to assemble a receptor- or drug-specific interactome in the context of substance use are encouraged. Studies will have direct implications for pharmacological therapeutics that target organelle dynamics for treatment of addiction.
Develop tools and functional probes to interrogate inter-organelle communications. To visualize intricate organelle networks and mechanisms impacted by addictive drugs and in models of substance use disorders.
Develop organelle targeted agents for selective delivery to the site of action in the cells. Targeting intracellular organelles at different stages of the addiction process to advance the development of specific intracellular delivery of therapeutic, diagnostic, or imaging agents to specific organelles in the context of substance use disorders (SUD).
Application and Submission Information
This notice applies to due dates on or after June 5, 2023 and subsequent receipt dates through September 8, 2026.
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:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.