Show simple item record

dc.contributor.authorPrusinski Fernung, Lauren
dc.date.accessioned2018-05-22T19:31:19Z
dc.date.available2018-05-22T19:31:19Z
dc.date.issued5/22/2018en
dc.identifier.urihttp://hdl.handle.net/10675.2/621813
dc.descriptionThe file you are attempting to access is currently restricted to Augusta University. Please log in with your NetID if off campus. Record is embargoed until 6/22/2028en
dc.description.abstractThough benign, uterine fibroids (UF) are the most significant benign neoplastic threat to women’s health and most common indication for hysterectomy. The elusive etiology of UF inhibits significant improvement in quality of care for affected women. Somatic mutations in the MED12 gene are currently thought to arise in myometrial stem cells (MSCs) converting them into UF tumor-initiating cells. Defective DNA repair increases the risk of tumorigenic somatic mutations, suggesting that additional mutations arising in fibroid stem cells (FSCs) ultimately contribute further to tumor growth and development. In addition, a significant ethnic disparity exists in UF prevalence, occurring in African American (AA) four times more as compared to Caucasian (CA) women, a phenomenon that has been observed for more than 120 years, but the molecular attributes behind UF’s ethnic disparity are still not fully realized. Our goal is to determine the mechanism by which the physiology of these human uterine MSCs is altered by changes in utero during early development of the epigenetic regulators of DNA-damage repair genes and how these stem cells lead to the origination of MED12 mutations and, ultimately, UF development later in adult life. Using a rat model of early-life environmental exposure, in which rats undergoing early uterine development were exposed to an endocrine disruptor, we compared the DNA repair capacity of exposed, "at-risk" myometrial stem cells to those from unexposed animals. In addition, we utilized human myometrial and fibroid tissue samples to characterize the myometrial stem cell populations from normal versus fibroid-containing uteri and compared the DNA repair capacity of human fibroid stem cells to the stem cells of adjacent myometrium. We determined that DNA repair in both exposed rat MSCs and human FSCs was decreased/altered compared to unexposed murine MSCs and human adjacent MSCs, respectively. In exposed rat MSCs, DNA double-strand break (DSB) repair was significantly impaired both in untreated cells and in cells in which DNA DSB damage was induced. Similar phenomena were observed in human FSCs as compared to adjacent MSCs. These data suggest impaired DNA repair in exposed MSCs and in human FSCs may contribute to initiation and perpetuation of UF tumorigenesis.
dc.subjectuterine fibroidsen
dc.subjecttissue-specific stem cellsen
dc.subjectDNA repairen
dc.subjectendocrine disruptorsen
dc.subjectdevelopmental reprogrammingen
dc.titleEarly Life Environmental Exposure and Hormonal Exposure and Race-Related Influence on the Human Stem Cell Populations in Fibroid and Myometrial Tissues Lead to Compromised Genomic Integrity and Increased Tumorigenesisen
dc.typeDissertationen
dc.contributor.departmentDepartment of Neuroscience and Regenerative Medicineen
dc.language.rfc3066en
dc.date.updated2018-05-22T19:31:19Z
dc.description.advisorAl-Hendy, Aymanen
dc.description.degreeDoctor of Philosophy with a Major in Molecular Medicineen
dc.description.committeeAl-Hendy, Ayman; Layman, Lawrence; McIndoe, Richard; Sakamuro, Daitoku; Yang, Qiweien
html.description.abstractThough benign, uterine fibroids (UF) are the most significant benign neoplastic threat to women’s health and most common indication for hysterectomy. The elusive etiology of UF inhibits significant improvement in quality of care for affected women. Somatic mutations in the MED12 gene are currently thought to arise in myometrial stem cells (MSCs) converting them into UF tumor-initiating cells. Defective DNA repair increases the risk of tumorigenic somatic mutations, suggesting that additional mutations arising in fibroid stem cells (FSCs) ultimately contribute further to tumor growth and development. In addition, a significant ethnic disparity exists in UF prevalence, occurring in African American (AA) four times more as compared to Caucasian (CA) women, a phenomenon that has been observed for more than 120 years, but the molecular attributes behind UF’s ethnic disparity are still not fully realized. Our goal is to determine the mechanism by which the physiology of these human uterine MSCs is altered by changes in utero during early development of the epigenetic regulators of DNA-damage repair genes and how these stem cells lead to the origination of MED12 mutations and, ultimately, UF development later in adult life. Using a rat model of early-life environmental exposure, in which rats undergoing early uterine development were exposed to an endocrine disruptor, we compared the DNA repair capacity of exposed, "at-risk" myometrial stem cells to those from unexposed animals. In addition, we utilized human myometrial and fibroid tissue samples to characterize the myometrial stem cell populations from normal versus fibroid-containing uteri and compared the DNA repair capacity of human fibroid stem cells to the stem cells of adjacent myometrium. We determined that DNA repair in both exposed rat MSCs and human FSCs was decreased/altered compared to unexposed murine MSCs and human adjacent MSCs, respectively. In exposed rat MSCs, DNA double-strand break (DSB) repair was significantly impaired both in untreated cells and in cells in which DNA DSB damage was induced. Similar phenomena were observed in human FSCs as compared to adjacent MSCs. These data suggest impaired DNA repair in exposed MSCs and in human FSCs may contribute to initiation and perpetuation of UF tumorigenesis.


Files in this item

Thumbnail
Name:
PrusinskiFernung_gru_1907E_100 ...
Size:
4.764Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record