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Understanding the miRNA response to opioid withdrawal and their uses as potential biomarkers for neonatal abstinence syndrome

Award Number: F30DA057094
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Understanding the miRNA response to opioid withdrawal and their uses as potential biomarkers for neonatal abstinence syndrome - Project Summary/Abstract Neonatal abstinence syndrome (NAS) is characterized by central nervous system hyperactivity that occurs when an infant experiences withdrawal from maternal opioid use at birth. Rates of NAS in the United States have skyrocketed amidst the opioid epidemic. Assessment and clinical management of NAS rely on subjective symptom scales, which may contribute to the prolonged hospital stays and poor neuro- developmental outcomes associated with NAS. Enhancing our knowledge about the molecular factors that regulate the biologic response to opioid withdrawal in developing infants will provide an opportunity to create objective clinical tests and novel therapies for this significant medical problem. To date, there is no biologic tool to determine the necessary morphine dose in withdrawing infants, or to predict which infants will experience neurodevelopmental delays. This is partly due to the fact that prior studies have largely focused on the molecular response to opioid administration in adults, rather than the response to opioid withdrawal in infants. Serum levels of certain micro-ribonucleic acids (miRNAs) are impacted by opioid administration in adults (e.g., let-7a, miR-146a, miR-192). These short, non-coding nucleic acids also regulate neurogenesis, neuronal progenitor cell (NPC) maturation, and cell survival by repressing target messenger RNAs in the Argonaute complex. My sponsor, Dr. Steve Hicks, MD, PhD has pioneered the use of salivary miRNAs as non-invasive markers for pediatric neurodevelopmental conditions. Most salivary miRNAs are derived from exosomes, which can arise from the cranial nerves that densely innervate the oropharynx. My preliminary data shows that several “opioid-responsive” miRNAs are perturbed in the saliva of infants with NAS relative to healthy infants. Further, I have developed an in vitro system of opioid withdrawal utilizing human NPCs that displays dose- related perturbations in miR-146a along with disruptions in NPC fate. Based on these findings, the central hypothesis of my fellowship application is that morphine withdrawal alters miRNA expression in the developing brain, which impairs neuronal maturation by mRNA translation via Argonaute binding. I also hypothesize that salivary levels of exosomal miRNAs from infants with NAS will be directly related to both the maximal dose of morphine required for symptom control, and neurodevelopmental outcomes at six months. I will test these hypotheses in two specific aims. First, I will perform a longitudinal cohort study of 50 infants with NAS to determine whether salivary miRNA levels within brain-related exosomes can be measured at admission to predict the maximum morphine dose required for symptom control, and again at discharge to predict neurodevelopmental outcomes at six months (Aim 1). Second, I will transfect miRNA mimics in my in vitro NPC design of opioid withdrawal, and assess the mechanism by which miRNAs impact the response to opioid withdrawal with immunocytochemistry, single-cell RNA sequencing, and an Argonaute pull-down assay (Aim 2).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Drug Use and Addiction Research Programs	000	4	8/7/2025	NON-COMPETING CONTINUATION	$54,538
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $35,864 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Drug Use and Addiction Research Programs	000	3	7/19/2024	NON-COMPETING CONTINUATION	$35,864
														Subtotal = $35,864

Issue Date FY: 2023 ( Subtotal = $34,500 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Drug Use and Addiction Research Programs	001	2	8/2/2023	NON-COMPETING CONTINUATION	$34,500
2023	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Drug Use and Addiction Research Programs	000	1	11/22/2022	NEW	$0
														Subtotal = $34,500

Issue Date FY: 2022 ( Subtotal = $33,477 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Drug Use and Addiction Research Programs	000	1	8/10/2022	NEW	$33,477
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Drug Use and Addiction Research Programs	001	1	8/10/2022	NEW	$0
														Subtotal = $33,477

Grand Total All Awards = $158,379

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Understanding the miRNA response to opioid withdrawal and their uses as potential biomarkers for neonatal abstinence syndrome

Award Number: F30DA057094

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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