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The Impact of High Adiposity on the Endometrial Progesterone Response and Metallothionein Regulation
The Impact of High Adiposity on the Endometrial Progesterone Response and Metallothionein Regulation
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151340
- ISBN
- 9798382760926
- DDC
- 574
- 저자명
- Murphy, Alina R.
- 서명/저자
- The Impact of High Adiposity on the Endometrial Progesterone Response and Metallothionein Regulation
- 발행사항
- [Sl] : Northwestern University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 159 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
- 주기사항
- Advisor: Kim, J. Julie.
- 학위논문주기
- Thesis (Ph.D.)--Northwestern University, 2024.
- 초록/해제
- 요약Obesity is a prevalent, systemic disease with deleterious effects on the female reproductive tract, including predisposing to abnormal uterine bleeding, decreasing fertility, and increasing the risk of endometrial cancer. Here, we sought to understand the effects of excess adipose on the benign endometrium. We developed a physiologic in vitro coculture system consisting of multicellular organoids of the benign human endometrium and adipose spheroids in the presence of estradiol, progesterone, and testosterone to mimic the menstrual cycle. Gene expression analysis of endometrial organoids under high adiposity conditions revealed downregulation of genes normally expressed in secretory endometrium, suggestive of an altered progesterone response. Genes associated with ion homeostasis and detoxification of reactive oxygen species were also downregulated, including the metallothionein (MT) family of genes. We demonstrated that MT gene expression in endometrial organoids was regulated by progesterone specifically in the epithelial cells, not in the stromal cells, and that progesterone receptor is recruited to the promoters of MT genes in endometrial epithelial cells. We illustrated the impact of MT dysregulation in the endometrium by silencing MT genes in endometrial epithelial cells, resulting in increased DNA damage. We examined native human endometrial tissue samples from premenopausal women with and without obesity to determine how MT expression correlates with obesity. Endometria from obese women displayed increased MT expression and oxidative damage in the endometrial stroma and not in the epithelium. Here, we show that the mechanism of MT regulation differs in endometrial epithelial and stromal cells. Our results reveal that exposing the endometrium to high adiposity can compromise the protective effects of progesterone, dysregulate MT genes in the endometrial epithelium, and leave the endometrium vulnerable to ROS-induced DNA damage. This study sheds light on the intricate interplay between adiposity and endometrial physiology. High adiposity or obesity can alter MT expression through different mechanisms: decreased progesterone response in the epithelial cells and increased oxidative stress in the stroma.
- 일반주제명
- Biology
- 일반주제명
- Genetics
- 일반주제명
- Cellular biology
- 일반주제명
- Biochemistry
- 일반주제명
- Obstetrics
- 키워드
- Metallothionein
- 키워드
- Gene expression
- 키워드
- Obesity
- 키워드
- Epithelial cells
- 기타저자
- Northwestern University Driskill Graduate Training Program in Life Sciences
- 기본자료저록
- Dissertations Abstracts International. 85-11B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211151340
■006m o d
■007cr#unu||||||||
■020 ▼a9798382760926
■035 ▼a(MiAaPQ)AAI31242182
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aMurphy, Alina R.
■24510▼aThe Impact of High Adiposity on the Endometrial Progesterone Response and Metallothionein Regulation
■260 ▼a[Sl]▼bNorthwestern University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a159 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-11, Section: B.
■500 ▼aAdvisor: Kim, J. Julie.
■5021 ▼aThesis (Ph.D.)--Northwestern University, 2024.
■520 ▼aObesity is a prevalent, systemic disease with deleterious effects on the female reproductive tract, including predisposing to abnormal uterine bleeding, decreasing fertility, and increasing the risk of endometrial cancer. Here, we sought to understand the effects of excess adipose on the benign endometrium. We developed a physiologic in vitro coculture system consisting of multicellular organoids of the benign human endometrium and adipose spheroids in the presence of estradiol, progesterone, and testosterone to mimic the menstrual cycle. Gene expression analysis of endometrial organoids under high adiposity conditions revealed downregulation of genes normally expressed in secretory endometrium, suggestive of an altered progesterone response. Genes associated with ion homeostasis and detoxification of reactive oxygen species were also downregulated, including the metallothionein (MT) family of genes. We demonstrated that MT gene expression in endometrial organoids was regulated by progesterone specifically in the epithelial cells, not in the stromal cells, and that progesterone receptor is recruited to the promoters of MT genes in endometrial epithelial cells. We illustrated the impact of MT dysregulation in the endometrium by silencing MT genes in endometrial epithelial cells, resulting in increased DNA damage. We examined native human endometrial tissue samples from premenopausal women with and without obesity to determine how MT expression correlates with obesity. Endometria from obese women displayed increased MT expression and oxidative damage in the endometrial stroma and not in the epithelium. Here, we show that the mechanism of MT regulation differs in endometrial epithelial and stromal cells. Our results reveal that exposing the endometrium to high adiposity can compromise the protective effects of progesterone, dysregulate MT genes in the endometrial epithelium, and leave the endometrium vulnerable to ROS-induced DNA damage. This study sheds light on the intricate interplay between adiposity and endometrial physiology. High adiposity or obesity can alter MT expression through different mechanisms: decreased progesterone response in the epithelial cells and increased oxidative stress in the stroma.
■590 ▼aSchool code: 0163.
■650 4▼aBiology
■650 4▼aGenetics
■650 4▼aCellular biology
■650 4▼aBiochemistry
■650 4▼aObstetrics
■653 ▼aMetallothionein
■653 ▼aGene expression
■653 ▼aEndometrial physiology
■653 ▼aObesity
■653 ▼aEpithelial cells
■653 ▼aProgesterone response
■690 ▼a0306
■690 ▼a0369
■690 ▼a0379
■690 ▼a0487
■690 ▼a0380
■71020▼aNorthwestern University▼bDriskill Graduate Training Program in Life Sciences.
■7730 ▼tDissertations Abstracts International▼g85-11B.
■790 ▼a0163
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17161326▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
