The purpose of this Notice is to inform potential applicants to the National Institute on Drug Abuse (NIDA) of special interest in research examining the roles of biomolecular condensates (BMCs) or their regulators in processes relevant to substance use disorders (SUDs) and/or HIV infection, latency, or pathogenesis.

Background

Biomolecular condensates (BMCs) are diverse and dynamic subcellular domains formed by liquid-liquid phase transitions in which multivalent proteins, RNAs, or proteins with intrinsically disordered regions (IDRs) nucleate subcellular regions with a distinct liquid phase in aqueous solution. BMCs have previously unrecognized and important roles in a wide variety of biological processes including regulation of gene expression, organization of subcellular structures in the nucleus and cytosol, and clustering of neurotransmitter-containing synaptic vesicles and voltage gated calcium channels at the synapse. Recent work indicates that multiple proteins implicated in neurodegeneration associated with pathological protein aggregation also participate in the formation of BMCs. There is emerging evidence that dendritic spines and synapses utilize BMCs in their formation and dynamics. Additionally, there is a recently discovered role for BMCs in modulation of receptor kinase signaling at membranes.

CNS BMCs and Substance Use Disorders.Much remains to be learned about the role of BMCs and their regulators in CNS functions including chromatin structure, gene expression, dendritic spine formation, synaptic function, neurodegeneration, regeneration, or subcellular localization of channels, receptors, or vesicles. Addictive substances impact many of these processes and could influence CNS functions in part via BMCs. Although a role for BMCs in receptor kinase signal transduction at the plasma membrane has been established, it is not known whether BMCs influence GPCR signal transduction, BDNF receptor function, or the functions of other signal transduction pathways relevant to addictive substances.

BMCs and HIV.There is much we do not know about BMCs in HIV biology. For example, it has recently been shown that vesicular stomatitis virus (VSV) exploits a nuclear BMC for efficient replication of the VSV RNA genome, but it is not known if HIV uses a BMC for a similar purpose. Despite the emerging role for BMCs in establishing and regulating chromatin structure in the nucleus, little is known about the potential involvement of BMCs in HIV/SIV infection, the formation or maintenance of HIV latency or whether HIV latency could be strengthened or diminished by manipulation of nuclear BMCs. Dysregulation of BMC-related processes also could be involved in the etiology of HIV-associated Neurocognitive Disorder (HAND).

Research Objectives

The purpose of this NOSI is to encourage the submission of research projects examining the roles of BMCs or their regulators in processes relevant to SUDs and/or HIV infection, latency, or pathogenesis.

It is anticipated that compelling projects will require interdisciplinary collaborations between individuals with expertise in BMCs and with significant knowledge of substance use and SUDs and/or HIV infection, replication, latency, or pathogenesis. Applicants are encouraged to establish such collaborations.

It is anticipated that investigations into the role of BMCs in substance use or SUD-relevant processes or HIV infection, replication, latency, or pathogenesis could uncover potentially novel mechanistic insights. In addition, work in this area may yield potentially new and unexpected targets that could be exploited to treat SUDs, HIV, or HIV-related pathological consequences.

Some examples of research projects appropriate for this NOSI include, but are not limited to:

SUD-relevant

• Development of technologies to improve identification, monitoring, or manipulation of BMCs or BMC regulators (including RNAs or proteins involved in BMC formation, dissolution, or composition) in SUD-relevant cell types or models.
• Exploration of the role of BMCs or BMC regulators in SUD-relevant processes, cells, or models including pre-synaptic function, post-synaptic function, vesicular regulation, RNA transport, neuronal plasticity, CNS development, neural growth factors, or functions in non-neuronal CNS cell types.
• Exploration of the roles of BMCs in opioid, cannabinoid, nicotinic, dopaminergic, or other signaling or gene expression pathways relevant to addictive substance use.
• Testing the role of BMCs in addictive processes using animal models of exposure to addictive substances including nicotine, cocaine, methamphetamine, stimulants, opioids, prescription drugs, cannabinoids, alcohol, or combinations of these drugs.
• In silicoor high throughput screening approaches to identify BMC proteins or their regulators that might function in SUD-relevant signal transduction or influence the functions of SUD-relevant receptors, channels, or other signal transduction components.
• Investigation of nuclear BMCs or their regulators in SUD-relevant gene expression of chromatin regulation. These nuclear BMCs could be involved in regulation of chromatin structure, nuclear bodies, transcription, splicing, or other nuclear processes.
• Approaches that develop novel ways to manipulate SUD-relevant BMCs or BMC function through pharmacological, genetic, targeting, or other strategies.

HIV-relevant

• Development of technologies to improve monitoring and/or manipulation of BMCs or BMC regulators in HIV/SIV infected or latent cells.
• Exploration of the role of BMCs or BMC regulators in HIV/SIV related processes including infection, replication, latency formation or maintenance, pathogenesis, or neurodegeneration (e.g. HAND).
• In silicoor high throughput screening approaches to identify HIV-relevant host or viral components of BMCs or their regulators.
• Investigation of nuclear BMCs or their regulators in HIV/SIV infection, replication, latency, treatment, or pathology. These nuclear BMCs could be involved in regulation of chromatin structure, nuclear bodies, transcription, splicing, or other nuclear processes.
• Investigation of BMCs in T cell function and how functions these might impact HIV/SIV replication or latency.
• Investigation of changes in CNS BMCs or their regulators in response to HIV/SIV or HIV therapies. Phenotypes might include morphological or functional changes to CNS cells, subcellular structures, dendritic spines, or synapses.
• Approaches that develop novel ways to manipulate HIV-relevant BMCs or BMC function through pharmacological, genetic, targeting, or other strategies.
• Projects investigating the role of BMCs in regulation of signal transduction pathways relevant to HIV.

SUD and HIV-relevant

• Exploration of BMCs or their regulators in biological processes impacted both by HIV/SIV and addictive substances in the CNS or immune system.
• Use of artificially engineered BMCs to deliver therapies or otherwise treat SUDs or HIV.

Application and Submission Information

This notice applies to due dates on or after June 5, 2019 and subsequent receipt dates through September 8, 2023.

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

PA-19-056: NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
PA-19-091: NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
PA-19-052: NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)
PA-19-053: NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
PAR-18-437: Cutting-Edge Basic Research Awards (CEBRA) (R21-Clinical Trial Optional)
PA-18-591: Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp - Clinical Trial Optional)

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-20-018” (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 the Scientific/Research, Peer Review, and Financial/Grants Management contacts in Section VII of the listed funding opportunity announcements.

Scientific/Research Contact(s)

John Satterlee, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: (301) 435-1020
Email: satterleej@nida.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)

Aida Vasquez
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-2154
Email: vasquez@mail.nih.gov