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Fibronectin Matrix as an Instigator of Endothelial Cell Dysfunction
Fibronectin Matrix as an Instigator of Endothelial Cell Dysfunction
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152017
- ISBN
- 9798384465362
- DDC
- 574
- 서명/저자
- Fibronectin Matrix as an Instigator of Endothelial Cell Dysfunction
- 발행사항
- [Sl] : Princeton University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 117 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-04, Section: B.
- 주기사항
- Advisor: Schwarzbauer, Jean E.
- 학위논문주기
- Thesis (Ph.D.)--Princeton University, 2024.
- 초록/해제
- 요약The extracellular matrix (ECM) is a 3-dimensional network of proteins, proteoglycans, and glycoproteins organized into complex structures that support tissue specific cell attachment, arrangement, and behavior. Fibronectin (FN) is a foundational ECM protein that is polymerized into fibrils by cells and helps coordinate cell adhesion, migration, and proliferation. FN is essential for cardiovascular development and supports angiogenesis in adults. Despite its noted role in vasculogenesis, the basement membrane, a highly organized ECM that underlies endothelial cells in established vasculature, notably lacks FN. However, in fibrosis, FN accumulates in the subendothelial space, disrupting the normal basement membrane architecture. Utilizing human umbilical vein endothelial cells (HUVECs) cultured on permeable Transwell membranes, we investigated how FN matrix accumulation impacts endothelial cell organization and function. We found the FN matrix assembled in this model is heterogenous and discontinuous, and sites of FN matrix accumulation, driven by exogenous FN supplementation, correlated with regional alterations to cell distribution and cell cycle entry. Time course analysis revealed that FN accumulation preceded other changes, demonstrating a causal link between FN accumulation and monolayer disruption. Functionally, FN accumulation increased the HUVEC monolayer permeability to large solutes and induced increased MDA-MB-231 cell attachment to the monolayer, due to the exposure of subendothelial matrix. These results demonstrate that FN mediates a disruption of endothelial cell barrier function, supporting the hypothesis that FN is causative of pathological vascular dysfunction in fibrosis. We subsequently demonstrate the utility of a FN targeting probe generated from a novel, phage-display derived peptide, for delivering and maintaining fluorescent signal to the FN matrix, thus expanding the toolbox for analyzing and targeting FN matrix.
- 일반주제명
- Molecular biology
- 일반주제명
- Cellular biology
- 일반주제명
- Immunology
- 키워드
- Fibronectin
- 키워드
- Cell adhesion
- 키워드
- Cell attachment
- 기타저자
- Princeton University Molecular Biology
- 기본자료저록
- Dissertations Abstracts International. 86-04B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211152017
■006m o d
■007cr#unu||||||||
■020 ▼a9798384465362
■035 ▼a(MiAaPQ)AAI31331929
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aResnikoff, Henry Alexander .
■24510▼aFibronectin Matrix as an Instigator of Endothelial Cell Dysfunction
■260 ▼a[Sl]▼bPrinceton University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a117 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-04, Section: B.
■500 ▼aAdvisor: Schwarzbauer, Jean E.
■5021 ▼aThesis (Ph.D.)--Princeton University, 2024.
■520 ▼aThe extracellular matrix (ECM) is a 3-dimensional network of proteins, proteoglycans, and glycoproteins organized into complex structures that support tissue specific cell attachment, arrangement, and behavior. Fibronectin (FN) is a foundational ECM protein that is polymerized into fibrils by cells and helps coordinate cell adhesion, migration, and proliferation. FN is essential for cardiovascular development and supports angiogenesis in adults. Despite its noted role in vasculogenesis, the basement membrane, a highly organized ECM that underlies endothelial cells in established vasculature, notably lacks FN. However, in fibrosis, FN accumulates in the subendothelial space, disrupting the normal basement membrane architecture. Utilizing human umbilical vein endothelial cells (HUVECs) cultured on permeable Transwell membranes, we investigated how FN matrix accumulation impacts endothelial cell organization and function. We found the FN matrix assembled in this model is heterogenous and discontinuous, and sites of FN matrix accumulation, driven by exogenous FN supplementation, correlated with regional alterations to cell distribution and cell cycle entry. Time course analysis revealed that FN accumulation preceded other changes, demonstrating a causal link between FN accumulation and monolayer disruption. Functionally, FN accumulation increased the HUVEC monolayer permeability to large solutes and induced increased MDA-MB-231 cell attachment to the monolayer, due to the exposure of subendothelial matrix. These results demonstrate that FN mediates a disruption of endothelial cell barrier function, supporting the hypothesis that FN is causative of pathological vascular dysfunction in fibrosis. We subsequently demonstrate the utility of a FN targeting probe generated from a novel, phage-display derived peptide, for delivering and maintaining fluorescent signal to the FN matrix, thus expanding the toolbox for analyzing and targeting FN matrix.
■590 ▼aSchool code: 0181.
■650 4▼aMolecular biology
■650 4▼aCellular biology
■650 4▼aImmunology
■653 ▼aExtracellular matrix
■653 ▼aFibronectin
■653 ▼aEndothelial cells
■653 ▼aCell adhesion
■653 ▼aCell attachment
■690 ▼a0307
■690 ▼a0379
■690 ▼a0982
■71020▼aPrinceton University▼bMolecular Biology.
■7730 ▼tDissertations Abstracts International▼g86-04B.
■790 ▼a0181
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17162482▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
