Stephani L. Stancil, PhD, APRN
Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Research Assistant Professor of Pediatrics, University of Kansas School of Medicine
Full BiographyMollie M Walton, MD
Fellow; Clinical Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine
Full BiographyStephani Stancil, PhD, APRN, Adolescent Medicine, and Mollie Walton, MD, Cardiology, both received Maternal and Pediatric Precision In Therapeutics (MPRINT) P30 subawards from Indiana University, which receives funding from the National Institutes of Health (NIH)’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
Dr. Stancil received a $150,000 award covering a project period of Aug. 1, 2024-July 31, 2025, for her project titled “Safe Detect: development and optimization of 19F-MRS to detect drug disposition in the pediatric brain”.
As Dr. Stancil explains, there are several reasons we need to learn more about drug disposition in the brain.
“It’s critical to uncovering the link between brain exposure and clinical response, tolerability, and safety, as well as enabling inquiry into mechanistic changes during dynamic periods of life such as childhood and pregnancy.”
Current ways of better understanding brain disposition, such as positron emission topography (PET) imaging, don’t directly measure brain concentrations following clinically-relevant dosing in humans and, the method includes radiation exposure, which should be minimized in children and those who are pregnant.
19F-magnetic resonance spectroscopy (19F-MRS) is a non-invasive MRI method that detects naturally-occurring, non-radioactive fluorine. The team leverages the existing fluorine(s) in each drug molecule to detect their MRS signal in living human brain without ionizing radiation. The number of fluorines in the drug molecule impacts the signal strength.
The study team’s pilot work with fluoxetine successfully quantified brain concentrations in adolescents across a range of doses and demonstrated 3-fold variability in brain concentration at any given dose.
The goal of the current project is to further develop 19F-MRS as safe, non-invasive, and sensitive tool to detect drug concentrations in the brain. Dr. Stancil and her team aim to increase the sensitivity of 19F-MRS, broaden the detectability of 19F-MRS to various fluorine-containing medicines, and determine the feasibility of using 19F-MRS in youth of different ages and sizes.
“The downstream applications of this technique are vast, including changing the landscape of drug development by generating data from a physiologic compartment not otherwise accessible (i.e., the brain), and enabling safer, more precise use of therapeutics,” explains Dr. Stancil.
Steve Leeder, PharmD, PhD, is a co-investigator on the project.
Dr. Walton received a $25,000 award covering a project period of Aug. 1, 2024-July 31, 2025, for her project titled “MARFAN: Maximizing Atenolol Response through Functional Assessment iNvestigations amongst connective tissue disorders”.
Marfan syndrome (MFS) is a genetic disorder that affects the body's connective tissues, which support organs, bones, and other tissues. Aortic root enlargement is a common and progressive feature of MFS and is associated with life-threatening aortic root dissection.
To mitigate this risk, initiation of prophylactic anti-hypertensive drug therapy is recommended and the beta blocker, atenolol, is commonly used. Unfortunately, patients continue to have suboptimal response to the drug therapy.
The human organic cation uptake transporters (OCT) 1 and 2 are influx transporters involved in the uptake of atenolol. This objective of this study is to determine the role of genetic variants (known as polymorphisms) on the cellular uptake and clearance of atenolol, which may affect drug disposition and clinical effect.
“This project will characterize the role of OCT1 and OCT2 on atenolol cellular uptake and test the hypothesis that OCT1 and OCT2 proteins with genetic polymorphisms, when expressed in vitro, will result in altered cellular uptake of atenolol relative to the reference genotype” explains Dr. Walton.
This approach utilizes transiently transfected OCT1 and OCT2 cell assays to perform time-dependent atenolol uptake experiments to generate kinetics information. Transient transfection is a process that introduces nucleic acids, such as DNA or RNA, into cells for a limited time.
“My goal is to provide a better understanding of polymorphisms associated with OCT1 and OCT2 expression and function as a means to individualize pharmacologic therapy for atenolol, as well as other OCT1 and OCT2-dependent drugs utilized in cardiovascular patients,” said Dr. Walton.
Dr. Walton is supported by the mentorship of Jon Wagner, DO, and Bruno Hagenbuch, PhD, University of Kansas Medical Center, who act as co-investigators on the project.
The Maternal and Pediatric Precision in Therapeutics (MPRINT) Hub is a national resource for expertise in maternal and pediatric therapeutics to conduct and foster therapeutics-focused research in obstetrics, lactation, and pediatrics. The MPRINT Hub consists of the Indiana University-Ohio State University Data and Model Knowledge and Research Coordination Center (IU-OSU DMKRCC) and two Centers of Excellence in Therapeutics (CETs): The Vanderbilt Integrated Center of Excellence in Maternal and Pediatric Precision Therapeutics (VICE MPRINT) and the University of California San Diego MPRINT Center of Excellence in Therapeutics. This work is funded by the National Institute of Health (NIH) P30HD106451.