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National Advisory Council on Drug Abuse (NACDA) Approved Concepts

A concept describes the purpose, scope, and objectives of a potential funding opportunity.  Approved concepts are usually developed into Requests for Applications (RFAs), in which funds are set aside by the Institute to stimulate a specific program of research.  Concepts are being posted to give interested researchers additional time to plan for application submissions. The NACDA conducts most, but not all, NIDA concept clearances. Concepts may also be cleared through other public venues.  Concepts cleared through other public venues are marked with an asterisk (*). 

Please send questions regarding specific concepts to the program contact listed in the description. Please also note that to avoid any conflicting information, once a concept has been finalized as a published RFA (or similar funding announcement), it is deleted from this early notification, concept clearance list.

Concept Index:

Avenir Award Program for Research on Substance Abuse and HIV/AIDS 

Posted: September 9, 2019

Background 

This concept request is for reissue of the NIDA DP2 program in HIV/AIDS research. The Avenir Award Program for Research on Substance Abuse and HIV/AIDS supports creative individuals who wish to pursue innovative research at the nexus of substance abuse and HIV/AIDS. The Avenir award is designed to complement the NIDA Avant-Garde award by focusing on early stage investigators. Avenir applicants may propose research in any area of high priority HIV/AIDS research that has the potential to open new areas of HIV/AIDS research and/or lead to new avenues for treatment and prevention of HIV/AIDS among substance abusers. 

Goal 

The program invites applications proposing innovative approaches in basic and clinical research areas, which have the potential to benefit substance using populations with or at risk for HIV/AIDS by reducing HIV incidence, improving therapies for HIV, reducing the impact of comorbid conditions, and ultimately, eradicating HIV. Examples of studies of relevance to drug abuse include: studies using populations with significant numbers of drug users or samples from drug using populations; studies using in vitro systems and/or animal models that test the effects of drugs of abuse on HIV pathogenesis, progression, or treatment; and studies to develop interventions or treatments that are tailored to substance using populations. The award will support those in an early stage of their career who may lack the preliminary data required for an R01 grant, but who propose high priority, high impact research, and who show promise of being tomorrow's leaders in the field. 

Redonna Chandler, Ph.D., AIDS Research Program 


Implementing the HIV Service Cascade for Justice-Involved Populations 

Posted: September 9, 2019

Background 

To reach the goal of ending the HIV epidemic in the United States, it is critical to understand, address, and bridge gaps in achieving viral suppression in populations that are disproportionately vulnerable to HIV. Justice-involved populations in the United States who inject drugs or have opioid use disorders (OUD) are at heighted risk for HIV. Community re-entry from a period of incarceration is a time of heightened risk for opioid relapse, mortality, HIV risk behaviors, and discontinuation of HIV treatment. Integrated care models that reduce or eliminate barriers to access to combined HIV/OUD prevention and treatment could be especially powerful in reducing HIV transmission, enhancing HIV viral suppression, and reducing other negative outcomes such as relapse and recidivism. 

Goal 

The goal of this initiative is to develop models of care that provide comprehensive and readily accessible HIV and substance use prevention and treatment services, tailored to the specific needs and unique risks for justice-involved populations. This initiative is expected to leverage infrastructure from NIDA’s new HEAL-funded Justice Community Opioid Innovation Network (JCOIN). The specific goal of the initiative would be to launch a multisite hybrid implementation-effectiveness trial focused on delivering a full continuum of HIV services for adults who use opioids in US community corrections (probation/parole) settings. Services would be inclusive of screening, pre-exposure prophylaxis (PrEP), highly active antiretroviral therapy (HAART), as well as medications for opioid use disorder (MOUDs). Mobile treatment vans and peer navigators would be a key component of the intervention design in this initiative. 

This initiative aligns with the NIH-OAR priority of reducing the incidence of HIV, and with the President’s objective to end the HIV epidemic by 2030. 

Minnjuan W. Flournoy Floyd, PhD, Division of Epidemiology, Services and Prevention Research 


Ending the Epidemic: New Models of Integrated HIV/AIDS, Addiction, and Primary Care Services 

Posted: September 9, 2019

Background 

HIV/AIDS, substance use disorders, mental health conditions, and other health conditions are all highly comorbid. Currently, these services are often delivered in multiple care settings, resulting in fragmented, uncoordinated care, which contributes to suboptimal treatment outcomes. The initiative would support the development of new models of care that function as one-stop-shops capable of integrating comprehensive services, including (but not limited to) HIV/AIDS services, addiction prevention and treatment services, and primary care services. 

Goal 

The goal of this FOA is to develop and test replicable, scalable organizational and systems level interventions to determine how best to provide comprehensive, integrated interventions to improve the health outcomes related to HIV and SUD. 

Applications to this FOA will be required to utilize implementation science informed approaches, with an emphasis on scalability, replicability, quality measurement, sustainability, and cost-effectiveness. Specifically, this initiative would support: (1) care models that integrate HIV screening, prevention, and engagement in care in substance use or primary care settings; or (2) care models that integrate substance use screening, prevention, and treatment in Ryan White Clinics or other HIV Services settings, including prevention-oriented settings such as STI clinics. Applicants will be strongly encouraged to develop models that provide comprehensive care across the full prevention to treatment continuum for both HIV/AIDS and substance use supports. For HIV/AIDS, this means treatment models should include screening, PrEP, and HAART. For substance use, this means care models that include screening, prevention services, and referral to pharmacotherapies as appropriate (e.g., all three FDA-approved MOUDs). 

This effort will be aligned with the Ending the AIDS Epidemic by 2030 initiative; therefore applications to this FOA will be geographically limited to CDC’s list of vulnerable counties and jurisdictions experiencing or at-risk of outbreaks. 

Minnjuan W. Flournoy Floyd, PhD, Division of Epidemiology, Services and Prevention Research 


Reducing Stigma Related to Drug Use in Human Service Settings 

Posted: September 9, 2019

Background 

Stigma related to drug use is a pervasive, well-documented problem in health care, public health, and social service settings. This contributes to a lack of attention to drug use screening, poor outreach to drug users, and insufficient engagement by drug users with services to treat, mitigate or prevent drug use consequences such as HIV infection. Stigma is variously defined as an identity marked by disgrace, disapproval or shame, which often leads to discriminatory treatment by others. Stigmas of interest here include: internalized stigma among drug users, stigma associated with providing services to drug users, and stigma toward drug users by providers or service settings. Stigma reduction interventions have been developed and, in some cases, implemented on a wide scale, but generally have not targeted drug users. HIV stigma reduction interventions primarily have targeted HIV as a disease or key populations where sexual transmission is the primary behavioral risk. Fortunately, a large literature on stigma exists in a variety of conditions (e.g., cancer, mental illness) which can provide functional conceptual lessons to help speed the development of new interventions addressing drug users. The growng recognition that stigma often is intersectional in nature provides ways to consider gender, race/ethnicity, sexual orientation, disease comorbidities and other factors that may help increase the breadth and depth of new intervention strategies. 

Goal 

This initiative is intended to stimulate research to reduce drug users’ self-stigma, providers’ stigma regarding service to drug users and stigma toward drug users from providers and provider settings. Providing an initiative in this areas will address significant research gap and will enable research and practice to advance in a variety of settings and contexts that serve drug users as well as address self-stigma among drug users and providers. 

Richard A. Jenkins, Ph.D., Division of Epidemiology, Services & Prevention Research 


Investigating the roles of biomolecular condensates (BMCs) in substance use disorders and/or HIV infection, latency, or pathogenesis 

Posted: September 9, 2019

Background 

One of the most exciting new areas of biological research concerns biomolecular condensates (BMCs)---diverse and dynamic subcellular domains formed by liquid-liquid phase transitions in which RNAs, multivalent proteins, or proteins with intrinsically disordered domains nucleate subcellular regions with a distinct liquid phase in aqueous solution. BMCs are now known to have previously unrecognized and important roles in a wide variety of biological processes including regulation of gene expression (Strom et al.,2017, Nature), organization of subcellular structures in the nucleus and cytosol (Shin and Brangwynne, 2017, Science), clustering of neurotransmitter-containing synaptic vesicles at the synapse (Milovanovic et al., 2018, Science), and clustering of voltage gated calcium channels at the synapse (Wu et al. Mol Cell 2019). Furthermore, there is emerging evidence that dendritic spines and synapses may utilize biomolecular condensates in their formation and dynamics (Feng et al. Biochem. 2018). Another new area of investigation is a recently discovered role for BMCs in receptor signaling at membranes. Several studies show that BMCs influence signal transduction in several critical receptor kinase pathways including: EGF receptor//Ras/MAPK (Huan et al. Science 2019), Nephrin/N-WASP/actin-related signaling (Case et al., Science 2019), and T cell receptor/SRC/actin (Su et al. Science 2019). BMCs may even facilitate noise filtering for some membrane signal transduction pathways (Martin and Mittag, Science 2019). 

Gaps: 

  • Despite the newly established effects of BMCs on receptor kinase signal transduction at the plasma membrane, it is not known whether BMCs influence GPCR signal transduction. 
  • It is not known if addictive substances utilize BMCs to mediate gene expression, synaptic, neurotransmitter, or other molecular or cellular changes in the CNS. 
  • It has recently been shown that vesicular stomatitis virus (VSV) exploits nuclear BMCs for efficient replication of the VSV RNA genome. It is not known if HIV uses BMCs for a similar purpose. 
  • Despite the exciting role for BMCs in establishing and regulating chromatin structure in the nucleus, little is known about the potential role for BMCs in the formation or maintenance of HIV latency or whether HIV latency could be strengthened or reversed by manipulation of nuclear BMCs. 
  • Recent work indicates that seven proteins implicated in neurodegeneration as the result of pathological protein aggregation (e.g. tau/Alzheimer’s Disease, HTT-polyQ/Huntington’s disease, Fus/ALS) also participate in the formation of BMCs (Elbaum-Garfinkle, JBC 2019; Shin and Brangwynne, Science 2017). Whether or not dysregulation of BMC-related processes also could be involved in the etiology of HIV-associated neurodegeneration (HAND) is not known. 

Goals 

To support exploratory research into the role of BMCs in the following areas: 

  • drug-mediated changes to dendritic spine/synapse function, or CNS chromatin structure or gene expression. 
  • GPCR signal transduction (e.g. opioid, cannabinoid, nicotinic, & dopamine receptors) 
  • HIV replication, latency formation or maintenance, or HIV pathogenesis (e.g. HAND) 

Significance: 

  • Mechanistic insights? 
  • Novel therapeutic targets? 

John Satterlee, Ph.D. Division of Neuroscience and Behavior 


Using imaging approaches to characterize HIV reservoirs in lymphoid tissues & CNS in the context of injection drug use 

Posted: September 9, 2019

Background 

HIV infection can occur through multiple routes including sexual transmission and IV drug use. However, it remains unclear whether the route of initial infection influences the latent reservoir in people living with HIV. In vivo imaging technologies have significantly improved our ability to visualize HIV reservoirs. In addition, advances in in situ hybridization now enable detailed characterization of latent HIV reservoirs at the tissue and cell level. 

Gaps: 

  • Lack of detailed information concerning the extent of HIV lymphoid & brain reservoirs 
  • Unclear whether the route of infection influences the HIV latent reservoir (e.g. IV drug vs sexual transmission) 

Goals 

To support exploratory and mechanistic projects that: 

  • Exploit advances in in situ or in vivo imaging techniques or related technologies 
  • Investigate latent lymphoid and brain HIV or SIV reservoirs in humans or primates 
  • Compare infection by injection drug versus other routes of infection 

Significance: 

  • Facilitate HIV CURE approaches in IV drug users and/or SUD patients, if HIV reservoirs are impacted by route of infection 
  • Enable monitoring of therapeutic strategies for HIV treatment 
  • Enable monitoring of HIV reservoir changes in response to addictive substances and their treatments 

Kavi Varthakavi., DVM, Ph.D., AIDS Research Program (ARP) 


HIV Pathology and Latency Studies Using Live Functional Behaving Human Cell Chimera Animal Brains 

Posted: September 9, 2019

Background 

HIV can be incorporated into host cell genomes after infecting the human brain. Even with constant combined antiretroviral therapy (cART) many infected brain cells, particularly microglia, can carry latent HIV virus and become a reservoir of the virus, with consequences of persistent neuropathology. Many HIV patients are also high-risk populations of licit and illicit drug users. The commonly abused drugs such as opioids, cannabinoids, methamphetamine, and nicotine target the CNS, impact neural circuit activities and neuroimmune systems. Comorbidity of substance use disorders and HIV persistence exacerbate the brain and cognitive disorders. The cellular and molecular mechanisms of how HIV enters or reactivates from latent phase in the presence of cART and abused substances in the brain, as well as the comorbid effects, are not well understood. Since HIV does not infect non-human cells, experimenting HIV infection and latency in functional live brains has been problematic using most animal models. 

Recent technical advancements have enabled generating human-mice chimeric brains by engrafting human iPSC-derived primitive neural progenitor cells and/or cord blood-derived microglial progenitor cells into neonatal mouse. In the chimeric brain, human neural progenitor cells or microglial cells differentiate and migrate throughout the mouse brain. Such successes provide opportunities to define the structure, function, genetics and plasticity of neural networks containing human tissue. It can also serve as a rodent model to study HIV infectivity, reservoir formation, and the neuropathogenesis of HIV infection. It can also allow the study of HIV and substance abuse comorbidity in the brain of a fully functional, awake, behaving animal from the single cell to neural circuitry levels. 

Goals 

  • Foster the development of using a chimeric rodent model to advance the studies of HIV virology and latency. 
  • Study HIV neuropathology and its comorbidity with SUD, and their impacts to human neurons, glia and microglia in a fully functional, awake, behaving animal from single cell to neural circuits levels, to behavior. 
  • Provide resources for optimizing and validating the chimera models for HIV studies and its eradication. 

Da-Yu Wu, Ph.D., Division of Neuroscience and Behavior 


Using Cutting Edge Tools to Study Mechanisms of Opioid Action in Rodent Brain Cells and Circuits 

Posted: September 9, 2019

Background

A wide variety of transformative tools that enable probing of CNS structure and function have been generated through BRAIN and other research efforts. Some of these tools, such as Campari, Tango, and FLARE, enable the unbiased identification of circuits and ensembles at the cellular level which are responsible for specific organismal functions and behaviors. Similarly, tools such as single cell transcriptomics, single cell epigenomics, and various spatial genomics approaches enable unprecedented characterization of cell types and associated molecular phenotypes in particular brain regions of interest. 

Gaps:

There is much we do not know about: 

  • Opioid responsive circuits and ensembles at the cellular level 
  • The effects of opioids on cellular and molecular phenotypes at the single cell level 

Opportunity: exploit newly available tools to address these two important gaps 

Goals

To support research projects that investigate how opioids change brain cells and circuits: 

  • Through unbiased approaches to identify CNS cell ensembles engaged by opioids and their connections (broad view) 
  • At the single cell level in brain regions (e.g. NAc, PFC) known to be involved in OUD (deep view) 
  • Data will be made publicly available to the scientific community, for data mining 

Significance: 

  • Will deliver foundational knowledge to improve our mechanistic understanding of opioid use disorder (OUD) 
  • Will inform the development of future approaches to treat patients with OUDs 

Olivier Berton, Ph.D. and John Satterlee, Ph.D., Division of Neuroscience and Behavior 


Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose

Posted: September 9, 2019

Background

Given the current opioid use and overdose crisis in the country, there is an urgent need to develop safer and more efficacious medications to treat opioid use disorders and overdose. This FOA was issued as RFA-DA-19-002 as part of the HEAL initiative and has been very successful in supporting the development of medications to treat those conditions.

Goal

The purpose of this FOA is to continue supporting research that accelerates the discovery and development of medications to prevent and treat opioid use disorders (OUD) and overdose. The goal is to advance medications closer to FDA approval. Applications may include preclinical or clinical research studies of small molecules or biologics that will have high impact and quickly yield the necessary results to advance closer to FDA approval medications that are safe and effective to prevent and treat OUDs and overdose.

Iván D. Montoya, M.D., M.P.H., Division of Therapeutics and Medical Consequences 


Assessing Effects of Cannabinoids on HIV-associated Neuroinflammation

Posted: February 15, 2019

Background

Acute cannabis administration is proposed to alleviate HIV-associated immune and neurological complications, although concerns remain about the aversive effects and impact of prolonged cannabis administration.  The potential beneficial actions of cannabis towards HIV-associated disease is based on positive observations of anti-oxidative, anti-excitotoxic, and anti-inflammatory properties in the study of models for several other neurodegenerative diseases.  However, existing data about the protective effect of cannabis is largely observational without causal evidence.  We have limited knowledge about dynamic changes along with the time course and pattern of administration, or with the status of the endocannabinoid (endoCB) system at treatment.  The therapeutic potential/benefit of cannabis on HIV pathogenesis has not been systematically investigated.  Questions remain about the integrity of the endoCB system during HIV pathogenesis or under substance use disorders to inform how the preconditions may impact the therapeutic potential of cannabis.  Further, a longitudinal design is necessary to determine the limits of cannabis for this treatment purpose. 

Goal

This initiative supports research that will elucidate the roles or limits of using cannabis to mitigate HIV associated neuroinflammation.  It will be carried out with preclinical and clinical neuroAIDS models, to understand the interrelationships among cannabis, biomarkers of endoCB and neuroinflammation, and chronic neuroimmune complications.

Yu (Woody) Lin, Ph.D. Division of Neuroscience and Behavior


Targeting Inflammasomes in Drug Abuse and HIV

Posted: February 15, 2019

Background

Neuroinflammation triggered by brain trauma, neurodegenerative diseases or other neurotoxicant-induced central nervous system (CNS) disorders including human immunodeficiency virus type-1 (HIV-1) infection initiates CNS innate immune responses.  HIV-1 penetrates the blood brain barrier, infects macrophages and microglial cells, and promotes a cascade of inflammatory responses including the formation of inflammasomes.

Inflammasomes are a complex of high molecular weight proteins within the cytosol of stimulated cells that mediate the activation of inflammatory cascades. In response to insults, Nod-like receptors (NLRs) recruit adaptor proteins and caspase-1 to assemble inflammasomes and process the release of pro-inflammatory cytokines IL-1b, IL-18 and IL-33. The NLRP3 inflammasomes are the most well-characterized that comprises NLRP3, apoptosis-associated speck-like (ASC) adapter protein, and the downstream effector protease procasepase-1.

Recent evidence suggests that chronic drug exposure, i.e., cocaine, methamphetamine and morphine, can induce inflammasome activation primarily mediated by NLRP3 within microglia. Additionally, emerging data suggest that HIV-1 infection can also prime inflammasome activation. Drug abuse, especially in association with HIV-1 infection, induces reactive oxygen species (ROS) production, impairs blood brain barrier integrity, and promotes monocyte transmigration. These upstream events exert synergistic effects that prime oligomerization and activation of inflammasome and release of pro-inflammatory cytokine IL-1b. Persistent inflammatory signaling pathways involved inflammasome formation and activation may lead to progressive loss of the functional capacity of the immune system. This could contribute to the pathogenesis that underlies HIV-associated neurocognitive disorders (HAND).

Goal

The scientific objective of this research is to delineate the role of inflammasomes in neuropathology produced by chronic drug exposure and HIV infection. Understanding the involvement of inflammasome in the immune activation may help identify molecular markers and CNS immune cells associated with HIV-1 infection or disease progression among substance abuse populations, as well as identify novel therapies to target inflammasome activation or suppression to treat neuroinflammation and immune dysregulation aroused in these processes.

Anne Tsai, Ph.D. Division of Neuroscience and Behavior

 

This page was last updated September 2019