Investigating the genetic network that regulates MU-opioid receptor signaling and behavioral responses to opioids

Active Project Grant Awarded Last action

Award ID
F31DA067087
Recipient
Awarding agency
Obligated
$46,624

Award facts

Assistance listing
93.279 Drug Use and Addiction Research Programs
Completion date 0% complete
Place of performance
Seattle, WA 98101, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
The opioid epidemic is one of the most severe public health crises in US history. While opioids are the most effective analgesics, their clinical use is significantly constrained by dependence and tolerance. Despite extensive research on regulators of opioid dependence and tolerance, IT remains uncertain whether larger more extensive gene networks regulate opioid signaling. The MU-opioid receptor (MOR), a g protein-coupled receptor, is the primary molecular target of opioids that mediates both analgesia and harmful side effects. To investigate MOR signaling, our lab built a novel transgenic c. Elegans model (tgmor) that expresses mouse MOR. This opioid-sensitive, whole-animal model is coupled to computationally automated assays to measure behavioral sensitivity to opioids. The tgmor model previously facilitated the first unbiased forward genetic screens targeting MOR and opioid responsive behavior, which identified multiple conserved regulators of MOR signaling. To broaden the scope and human relevance of our genetic approach, the grill lab recently generated a humanized tgmor c. Elegans model (htgmor) that expresses human MOR and is a second-generation c. Elegans opioid model. With this new humanized model, my proposal aims to investigate and characterize the genetic network that regulates MOR signaling and opioid-induced behaviors. Aim 1 will use reverse genetics to investigate how a potential genetic mediator and regulator of MOR signaling influence opioid-induced behavior in htgmor c. Elegans. We will use unbiased, computationally automated behavioral assays to evaluate the opioid sensitivity of multiple htgmor cripsr null mutants for both the selected putative mediator and regulator of MOR signaling. Transgenic rescue experiments will confirm genetic effects on opioid sensitivity. Aim 1 will also test functional redundancy between the potential regulator and its homolog. Aim 2 is based on our completed forward genetic screen that isolated htgmor mutants with altered opioid sensitivity. I will identify, evaluate, and validate htgmor mutants to potentially reveal novel players that regulate MOR signaling and opioid-induced behaviors. I will examine three htgmor hypersensitive mutants that i isolated from our completed forward genetic screen using unbiased, computationally automated behavioral assays. I will map and identify genetic lesions causing opioid hypersensitivity in htgmor mutants by integrating whole-genome sequencing with phenotypic selection. Candidate, mapped mutations will be further validated by using crispr engineering to introduce single mutations of interest into parental htgmor animals. Opioid sensitivity will then be evaluated for htgmor crispr edited mutants. Overall, our innovative new humanized htgmor c. Elegans model will be used for reverse genetic and unbiased, large-scale forward genetic approaches to better understand the gene networks that regulate MOR signaling and opioid-induced behavior. Our long-term goal is to uncover novel regulators of MOR signaling that can be targeted to manage the adverse side effects of opioids.

Quick answers

Who received award F31DA067087?

F31DA067087 was awarded to Seattle Children's Hospital by National Institute on Drug Abuse (National Institutes of Health) on January 17, 2027.

How much is award F31DA067087 worth?

$46,624 has been obligated on F31DA067087.

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