NIH – Extracellular Vesicles and Substance Use Disorders (R01, R21)

April 21, 2017 by School of Medicine Webmaster

The following description was taken from the R01 version of this FOA:

Secreted extracellular vesicles (EVs) play roles in many biological processes.  In some cases these vesicles appear to travel through the body and fuse with specific cell types to deliver nucleic acid, protein or other cargoes that may alter cellular phenotypes.  In the nervous system, EVs may function in neuronal-glial communication, synaptic plasticity, immune surveillance, or as endocannabinoid carriers.  However the role of EVs in CNS disorders and SUDs is not well characterized.

In addition, EVs from body fluids such as blood, cerebrospinal fluid, urine, saliva, semen, breast milk, and amniotic fluid could provide useful biomarkers for a variety of human diseases including CNS disorders.  Understanding EV dynamics and cargoes across the trajectory of addiction may help to identify useful biomarkers for diagnosing: 1) drug use history (the type, quantity, and/or frequency of drug use), 2) the stage/trajectory of addiction (e.g. escalation, withdrawal, incubation, craving, relapse), or 3) both.  Also EVs may be useful for in vivo targeting of cargoes such as nucleic acids or small molecules of therapeutic value to specific organs or cell types.

Research Objectives

The purpose of this FOA is to encourage research projects that investigate the interplay between EVs and SUDs.  In particular, NIDA is interested in the potential utility of EVs with respect to understanding neuroplastic mechanisms relevant to SUDs or as biomarkers or therapeutics.

Proposed projects are expected to meet the following two criteria: 1) the major thrust of the application should involve extracellular vesicles or EV biogenesis machinery; and 2) at least one aim or sub-aim should involve exposure to addictive substances, or analysis of samples from patients with substance use or SUDs. Addictive substances of interest include: nicotine, cocaine, stimulants, opioids, prescription drugs, cannabinoids, or use of multiple substances (including alcohol).  Applications focused solely on alcohol exposure should not apply through this FOA.

Project teams should include researchers with expertise in both EVs and in SUDs.

The choice of biological system for the proposed investigations should be well justified.  Applicants may propose studies that investigate body fluids or tissues from human patients, primates, or rodents.  Primary cells, cell lines, organoids, or other systems may also be proposed for investigation, if appropriately justified.  Patient samples should be well characterized for stage/trajectory of SUD, type(s) of drug used, co-occurring conditions, gender, and age.

Applicants focused on behavioral assessments in mammals should ensure that they include one or more behavioral assays of drug reward and/or reinforcement (e.g. conditioned place preference, self-administration, compulsive drug seeking, or drug seeking in the face of negative consequences).  In addition to testing drug-seeking behaviors, applicants are encouraged to analyze other relevant behavioral phenotypes.

Applicants with preliminary data may wish to apply to this R01 FOA.  High risk/high payoff projects that lack preliminary data are most appropriate for the companion R21 FOA.

Some relevant topics of investigation could include, but are not limited to, the following:

Extracellular vesicles, biological processes and chronic drug exposure

  • How are CNS-derived EVs generated and transported? What are the molecular mechanisms by which they traffic and enter cells?  What are the molecular mechanisms by which they influence target cell phenotypes?  How does exposure to addictive substances influence these processes?
  • What are the cargoes of CNS-derived EVs (e.g. miRNA, circRNA, lncRNA, lipids, proteins, or metabolites)?  What are the pathways and/or covalent modifications involved in establishing these cargoes?  How does exposure to addictive substance influence CNS-derived EV cargoes?
  • Can tools or technologies be developed to enable classification or characterization of single EVs or small numbers of EVs?  Can in vivo sensors be developed to follow CNS EV biogenesis, transport, uptake, or impact on target cells? How can we better understand SUDs using these tools?
  • What are the physiological roles of EVs in the nervous system with respect to neuronal-glial interactions?  How are these different in drug-reinforced animals?
  • How do EVs impact the neuroimmune system or mediate neuroinflammatory or neuroprotective responses?  Are they affected by exposure to addictive substances?
  • What roles do EVs play in regulation of brain energetics, metabolism, or waste/toxin clearance?  Does exposure to addictive substances influence these roles?
  • What is the role of EVs in normal endocannabinoid signaling in the nervous system?  Do addictive substances impact this signaling?  Are endocannabinoids or other EV components involved in transducing molecular phenotypes in target cells?
  • What is the role of extracellular vesicles or EV biogenesis in different phases of addiction or in other relevant neuroplastic processes?
  • How do EVs influence brain development and/or developmental signaling pathways (e.g. Notch, Wnt, or Hedgehog)?  Do addictive substances alter these processes?
  • Do EVs play a role in transport of retrotransposons and is this influenced by addictive substances?
  • Do EVs in the nervous system interact with peripheral tissues or vice versa?  Do addictive substances impact these interactions?
  • Do EVs play a role in the transmission of transgenerational phenotypes relevant to SUDs?
  • What are the roles of EVs or EV biogenesis in HIV infection, transmission, latency, persistence, or disease progression?  How might these roles be influenced by exposure to addictive substances?

Deadlines:  August 15, 2017, January 16, 2018, August 15, 2018, January 15, 2019, August 15, 2019, January 15, 2020; letters of intent are due 30 days prior to the deadline

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Filed Under: Funding Opportunities