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NONHUMAN PRIMATES AS A TRANSLATIONAL MODEL OF ENDOMETRIOSIS AND ITS EFFECTS ON WOMEN'S HEALTH

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abstract
Endometriosis is a chronic, inflammatory gynecologic disease defined as the presence of uterine lining outside of the uterus. It affects approximately 10% of reproductive-aged women and symptoms include pain, infertility, and heavy or irregular menses. Endometriosis lesions are characterized by excess iron content and macrophage infiltration. Despite decades of endometriosis research, little is known about macrophage contribution to disease progression or the systemic effects of endometriosis on other physiologic processes. The project objectives were to use a nonhuman primate (NHP) model of endometriosis to address gaps in knowledge surrounding tissue macrophage function, endometriosis and eutopic endometrium metabolism, and systemic iron metabolism. The overall hypothesis for this research was that macaque NHPs provide a highly translational platform for studying endometriosis and its effects on overall health in women. Macrophage function in endometriosis tissue was studied using NHP archived tissue, an in vitro cell culture assay, and RT-qPCR. Endometrium and endometriosis tissue metabolism was analyzed using isolated mitochondrial respirometric analysis and targeted metabolomics. The effects of endometriosis on systemic iron metabolism were identified using NHP and human medical records, NHP tissue histomorphometry, and serum ELISAs. In endometriosis tissue, macrophage density correlated with nerve fiber density and iron concentration. These relationships among macrophages, nerves, and iron provide insight into the composition of endometriosis tissue and may be important for studying disease pathogenesis. The cell culture protocols developed in this study were the initial steps to further establish an endometriosis macrophage function assay. Endometrium and endometriosis tissue from NHPs with endometriosis had decreased mitochondrial respiration and metabolism, but the cause of these changes remains unknown. Finally, NHPs with endometriosis had hematologic evidence of anemia, and systemic iron depletion was identified as the major mechanism. Systemic iron depletion despite a high iron diet suggests oral iron supplementation alone is insufficient to replace iron stores. Overall, the information presented in this thesis represents the initial steps for more accurately modeling macrophage function in endometriosis, identifies decreases in mitochondrial function and metabolites in endometrium and endometriosis tissue, and highlights systemic iron depletion as a possible sequella of endometriosis. Future research will address the areas of multidimensional macrophage function assay development, endometrial biology, and iron replenishment strategies for women with endometriosis.
subject
Endometriosis
Iron
Macrophage
Metabolomics
Mitochondria
Nonhuman primates
contributor
Atkins, Hannah (author)
Caudell, David L (committee chair)
Appt, Susan E (committee member)
McClain, Donald (committee member)
Kock, Nancy D (committee member)
Taylor, Robert N (committee member)
date
2018-05-24T08:36:17Z (accessioned)
2020-05-23T08:30:19Z (available)
2018 (issued)
degree
Molecular Medicine and Translational Science (discipline)
embargo
2020-05-23 (terms)
identifier
http://hdl.handle.net/10339/90750 (uri)
language
en (iso)
publisher
Wake Forest University
title
NONHUMAN PRIMATES AS A TRANSLATIONAL MODEL OF ENDOMETRIOSIS AND ITS EFFECTS ON WOMEN'S HEALTH
type
Dissertation

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