Manasi Malik

ORCID

http://orcid.org/0000-0002-4203-962X

Date of Award

Spring 5-15-2023

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Oxytocin is a nonapeptide hormone that modulates social behavior, mediates the lactation reflex, and induces and strengthens uterine contractions. Each year, oxytocin is administered to about half of laboring patients for induction and augmentation, and to almost all patients for prevention of post-partum hemorrhage – a total of four million patients per year in the United States alone. However, response to oxytocin varies widely between individuals, and complications including uterine hyperstimulation, uterine atony, required Cesarean section, and postpartum hemorrhage can arise from either excessive or inadequate oxytocin response. To avoid these adverse events, it is critically important to identify individuals at risk for aberrant oxytocin response and develop strategies to improve outcomes in these patients.In this dissertation, I first sought to determine the effects of common missense genetic variants in the oxytocin receptor (OXTR) gene on oxytocin response. I screened prevalent genetic variants in OXTR and found that five variants alter calcium signaling and β-arrestin recruitment in cells. Three of these five variants had differential effects on calcium signaling and β-arrestin recruitment, leading to imbalance between activation and desensitization of the OXTR. Molecular dynamics simulations showed that these three variants cause conformational changes that are consistent with the signaling changes we observed in cells. Overall, these data show that OXTR variants alter oxytocin response, and suggest that individuals with these genetic variants may benefit from personalized oxytocin dosing. In the second part of this dissertation, I investigated the role of OXTR trafficking in determining oxytocin responsiveness. OXTR genetic variants that impair OXTR trafficking decrease maximal oxytocin response in transfected cells. I investigated whether small molecule modulators of OXTR and the closely related vasopressin receptor family could act as pharmacological chaperones for OXTR, increasing the cell surface localization of the wild type OXTR and rescuing the trafficking defects in variant OXTR. Treatment with the oxytocin/vasopressin antagonists increased cell surface localization of variant OXTR and rescued oxytocin signaling. The increase in OXTR cell surface localization and oxytocin responsiveness could also be observed in immortalized and primary human myometrial cells. Overall, these results show that pharmacological chaperones can enhance trafficking and function for both wild type and variant OXTR. This work presents a novel therapeutic strategy to improve the efficacy of oxytocin use in patients predicted to respond poorly due to genetic or environmental factors.

Language

English (en)

Chair and Committee

Sarah K. England

Committee Members

Thomas J. Baranski, Cristina de Guzman Strong, Joseph D. Dougherty, Princess I. Imoukhuede,

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