NIH – Genetic analysis of non-human animal models to understand the genomic architecture of substance use disorders and addictive behaviors (U01 Clinical Trial Not Allowed)

May 23, 2018 by School of Medicine Webmaster

There are strong heritable components to the array of phenotypes and endophenotypes associated with addictive behaviors and substance use disorders, with emerging human genome-wide studies identifying variants associated with several of these phenotypes. Classic behavioral genetics studies indicate that alleles influencing addiction-related phenotypes and endophenotypes can be identified in model organisms, providing the basis for the discovery of genes influencing these human phenotypes. Animal models provide an opportunity to identify targeted and measurable aspects of the genetics, epigenetics, physiology and brain function that influence behaviors associated with substance use disorders.

In addition to being used as a method to discover genes associated with addictive behaviors, model organism studies can be designed to tease out the relationships among variants and environmental components of substance use disorders, including substance of abuse, genetic background, gene x gene (GxG; epistasis), gene x environment (GxE), gene x drug (GxD), and other tractable environmental factors, such as genetic background that are not as easily accomplished in human genetic studies. These strong model systems capture the cellular context, identify tissue and cell-specific hallmarks, delineate relevant circuitry, help to understand longitudinal measures, and test hypotheses generated by human genetic studies. In addition, they facilitate a systems approach and can be used to develop new methods to integrate various levels of data (e.g. genomics, epigenomics, transcriptomics, behavioral, environmental), delineate epistatic, GxE, and GxD interactions at the organismal, tissue, circuit and cellular levels.

Research Scope and Objectives

This announcement encourages applications for projects aimed at the discovery of allelic variants, genomic alterations, and functional changes associated with addictive behaviors in non-human animals through systems studies that employ genetic and genomics strategies. We also encourage applications that take genetic and/or genomics approaches to integrate data, delineate gene networks, and uncover the function of known or newly discovered genetic or epigenetic variants.

The proposed projects should be based on phenotypes relevant to addictive behaviors and processes associated with substance use disorders. Vulnerability phenotypes are defined as individual differences that convey increased propensity to acquire, maintain, or escalate to uncontrollable, compulsive drug intake or increased vulnerability to relapse to drug seeking and drug-taking following a period of abstinence. Vulnerability phenotypes may be defined behaviorally or neurobiologically, must have demonstrated heritability, and be suitable for variant, gene, and/or gene network discovery. The following are examples of appropriate phenotypes; however, this is not an inclusive listing and there may be others:

  • High drug sensitivity, reactivity or preference
  • Preference or sensitivity for non-drug rewards
  • Somatic and affective drug withdrawal
  • Novelty preference or novelty seeking
  • Increased incentive motivation for reward-related stimuli
  • Sensitivity to develop escalation of drug taking
  • Impulsivity
  • Poor cognitive flexibility (e.g., reversal learning, set shifting, etc.)
  • Resistance to punishment during drug-seeking
  • Persistent responding in the absence of drug
  • Heightened relapse and reinstatement
  • Enhanced stress reactivity
  • Disrupted circadian rhythms
  • Aversion to drug

Vulnerability phenotypes that have been identified by individual differences in neurobiological substrate or mechanisms (structural, functional, chemical) that can be genetically mapped are also appropriate.

It is becoming clear that modifier loci and genetic background influence the presentation of various phenotypic traits associated with substance use disorders and addictive behaviors. Studies that aim to identify the genetic architecture of background genes and modifier loci are appropriate for this FOA, including studies proposing to use gene-editing, diverse backgrounds and other genetic methods.

Studies employing methods to integrate multiple levels of data to discover gene networks; GxE, GxG, and GxD interactions; and those proposing new methods to uncover these interactions, including those focusing on specific cell types, relevant tissues and neuronal circuits are also appropriate to this FOA.

Investigators are strongly encouraged to discuss their applications with the Scientific/Research contact listed in this FOA before submission.

Deadlines:  August 21, 2018, March 19, 2019; August 21, 2019, March 19, 2020; August 21, 2020, March 19, 2021


Filed Under: Funding Opportunities