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Cellular and Extracellular Matrix Mechanisms Underlying Ovarian Aging
Cellular and Extracellular Matrix Mechanisms Underlying Ovarian Aging
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151312
- ISBN
- 9798382759869
- DDC
- 574
- 서명/저자
- Cellular and Extracellular Matrix Mechanisms Underlying Ovarian Aging
- 발행사항
- [Sl] : Northwestern University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 206 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
- 주기사항
- Advisor: Duncan, Francesca E.
- 학위논문주기
- Thesis (Ph.D.)--Northwestern University, 2024.
- 초록/해제
- 요약Aging is associated with cell and tissue deterioration that contributes to impaired organ function and the ovary is unique in that it is the first organ to exhibit overt signs of aging. Ovarian aging leads to infertility due to decreased gamete quantity and quality, but also results in blunted endocrine function, which can have adverse effects on overall health. The effects of female reproductive aging are well characterized at the level of the gamete. However, gamete quality is dependent on the complex microenvironment of the ovarian stroma. The overarching goal of this thesis was to understand cellular and extracellular matrix mechanisms of aging centered in the ovarian stroma. The aging ovary becomes fibrotic and stiff, due in part to increased collagen and decreased hyaluronan. Still, the ovarian extracellular matrix (ECM) is composed of hundreds of proteins, glycoproteins, and glycans. In Chapter 2, we discuss our use of label-free, quantitative proteomic methods to gain an unbiased and comprehensive profile of age-associated changes to the murine ovarian proteome and ECM. We identified 383 proteins that were significantly altered in the mouse ovary with age, including 58 ECM proteins. Several ECM proteins upregulated with age were previously implicated in fibrosis in other organs, providing a list of candidates for future studies investigating age-related ovarian fibrosis. Pathways regulating DNA metabolism and translation were downregulated with age, whereas pathways involved in ECM remodeling and immune response were upregulated. Our findings suggest a novel interplay between the ECM and the immune system in the ovary, in addition to identifying putative markers of immune populations only present in the ovary with advanced reproductive age. In addition to ECM components, the ovarian stroma is also composed of heterogenous cell populations that have been difficult recapitulate in in vitro models. In Chapter 3, we discuss our establishment of a novel organoid model of the ovarian stroma. Murine ovarian somatic organoids maintained diverse cell populations, produced an ECM, and secreted hormones, as well as cytokines. To utilize this model to inform mechanisms of aging, we generated ovarian organoids from young and old mice in parallel and found that organoids from old mice exhibited impaired aggregation and decreased growth. Organoids exhibited age-dependent alterations to relative cell composition and function, including attenuated hormone production with age. Pathways associated with the actin cytoskeleton were upregulated in primary ovarian somatic cells from old mice, whereas pathways associated with cell adhesion were downregulated. These findings are suggestive of an ageassociated increase in cytoskeletal stiffness and in fact, pharmacologic modulation of the actin cytoskeleton partially improved aggregation of organoids generated from old mice. Overall, the work performed in this thesis has identified proteins driving ovarian aging phenotypes for further investigation and potential therapeutic targeting. Moreover, we have created an in vitro model of the ovarian stroma that can be applied to study ovarian physiology and pathologies. Lastly, these findings have revealed cytoskeletal stiffness to be a cellular mechanism contributing to ovarian aging.
- 일반주제명
- Cellular biology
- 일반주제명
- Aging
- 일반주제명
- Physiology
- 키워드
- Organoid
- 키워드
- Ovarian stroma
- 키워드
- Ovary
- 키워드
- Proteomics
- 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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■020 ▼a9798382759869
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aDipali, Shweta S.▼0(orcid)0000-0002-4964-4822
■24510▼aCellular and Extracellular Matrix Mechanisms Underlying Ovarian Aging
■260 ▼a[Sl]▼bNorthwestern University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a206 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-11, Section: B.
■500 ▼aAdvisor: Duncan, Francesca E.
■5021 ▼aThesis (Ph.D.)--Northwestern University, 2024.
■520 ▼aAging is associated with cell and tissue deterioration that contributes to impaired organ function and the ovary is unique in that it is the first organ to exhibit overt signs of aging. Ovarian aging leads to infertility due to decreased gamete quantity and quality, but also results in blunted endocrine function, which can have adverse effects on overall health. The effects of female reproductive aging are well characterized at the level of the gamete. However, gamete quality is dependent on the complex microenvironment of the ovarian stroma. The overarching goal of this thesis was to understand cellular and extracellular matrix mechanisms of aging centered in the ovarian stroma. The aging ovary becomes fibrotic and stiff, due in part to increased collagen and decreased hyaluronan. Still, the ovarian extracellular matrix (ECM) is composed of hundreds of proteins, glycoproteins, and glycans. In Chapter 2, we discuss our use of label-free, quantitative proteomic methods to gain an unbiased and comprehensive profile of age-associated changes to the murine ovarian proteome and ECM. We identified 383 proteins that were significantly altered in the mouse ovary with age, including 58 ECM proteins. Several ECM proteins upregulated with age were previously implicated in fibrosis in other organs, providing a list of candidates for future studies investigating age-related ovarian fibrosis. Pathways regulating DNA metabolism and translation were downregulated with age, whereas pathways involved in ECM remodeling and immune response were upregulated. Our findings suggest a novel interplay between the ECM and the immune system in the ovary, in addition to identifying putative markers of immune populations only present in the ovary with advanced reproductive age. In addition to ECM components, the ovarian stroma is also composed of heterogenous cell populations that have been difficult recapitulate in in vitro models. In Chapter 3, we discuss our establishment of a novel organoid model of the ovarian stroma. Murine ovarian somatic organoids maintained diverse cell populations, produced an ECM, and secreted hormones, as well as cytokines. To utilize this model to inform mechanisms of aging, we generated ovarian organoids from young and old mice in parallel and found that organoids from old mice exhibited impaired aggregation and decreased growth. Organoids exhibited age-dependent alterations to relative cell composition and function, including attenuated hormone production with age. Pathways associated with the actin cytoskeleton were upregulated in primary ovarian somatic cells from old mice, whereas pathways associated with cell adhesion were downregulated. These findings are suggestive of an ageassociated increase in cytoskeletal stiffness and in fact, pharmacologic modulation of the actin cytoskeleton partially improved aggregation of organoids generated from old mice. Overall, the work performed in this thesis has identified proteins driving ovarian aging phenotypes for further investigation and potential therapeutic targeting. Moreover, we have created an in vitro model of the ovarian stroma that can be applied to study ovarian physiology and pathologies. Lastly, these findings have revealed cytoskeletal stiffness to be a cellular mechanism contributing to ovarian aging.
■590 ▼aSchool code: 0163.
■650 4▼aCellular biology
■650 4▼aAging
■650 4▼aPhysiology
■653 ▼aOrganoid
■653 ▼aOvarian stroma
■653 ▼aOvary
■653 ▼aProteomics
■653 ▼aReproductive aging
■690 ▼a0379
■690 ▼a0493
■690 ▼a0719
■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=T17161118▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
