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Extracellular Matrix Regulation of the Neutrophil Inflammatory Response
Extracellular Matrix Regulation of the Neutrophil Inflammatory Response
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104813
- ISBN
- 9798291573334
- DDC
- 616.079
- 서명/저자
- Extracellular Matrix Regulation of the Neutrophil Inflammatory Response
- 발행사항
- [Sl] : University of Colorado at Boulder, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 174 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-02, Section: B.
- 주기사항
- Advisor: Hind, Laurel E.
- 학위논문주기
- Thesis (Ph.D.)--University of Colorado at Boulder, 2025.
- 초록/해제
- 요약Bacterial infections are a leading cause of death globally. This is due not only to the rising prevalence of antimicrobial resistance, but also because of the opportunistic nature of many bacteria allowing them to take advantage of people with diseases that compromise their immune systems, such as those afflicted with cancer, fibrosis, and cardiovascular diseases. Consequently, there is an urgent need to develop non-antibiotic treatments that will improve the survivability of bacterial infections. Targeting neutrophils poses an interesting avenue for therapeutic development as they are a major driver of the body's natural immune response to bacterial infections. In healthy individuals, neutrophils effectively trap and kill invading bacteria within hours of an infection occurring. However, dysregulated neutrophil function contributes to the pathogenesis of several diseases, leaving people susceptible to severe infections. Thus, targeting the neutrophil response to combat bacterial infections may greatly improve patient outcomes. To effectively design such therapeutics, it is imperative to understand the factors that regulate the neutrophil response. Interestingly, diseases associated with neutrophil dysregulation are often accompanied by changes to the extracellular matrix (ECM). While it is known that properties of the ECM regulate cell behavior, the extent to which aspects of the ECM affect the neutrophil response to bacteria remains incomplete. The ECM is a complex network of macromolecules making it difficult to study how specific aspects of the ECM affect neutrophil behavior.In this work, we employ a biologically inspired infection-on-a-chip microfluidic device to investigate how collagen concentration, enzymatic crosslinking of collagen, and the combination of various matrix proteins in the ECM affect elements of the neutrophil response to bacteria. We found that collagen concentration regulates neutrophil extravasation and migration in an endothelial cell-dependent manner. Additionally, lysyl oxidase, an enzyme that crosslinks collagen fibrils, decreased neutrophil extravasation but did not affect the migration patterns of extravasated neutrophils. This may be due to the enzyme inhibiting TGF-β1 signaling, a potent neutrophil chemoattractant. Lastly, we observed no difference in neutrophil extravasation into collagen matrices supplemented with fibronectin and laminin; however, the combinations of these proteins differentially regulated neutrophil migration in the ECM during the later hours of an infectious response.Together these data underscore the ECM as an active regulator of the neutrophil response and highlights the value of using physiologically relevant microfluidic systems for investigating intricate aspects of neutrophil biology that are traditionally inaccessible via simple in vitro systems and in vivo animal models. Further development of such tools will lead to a more complete understanding of neutrophil biology and ultimately intelligent therapeutic designs to correct neutrophil dysregulation.
- 일반주제명
- Immunology
- 일반주제명
- Physiology
- 일반주제명
- Cellular biology
- 일반주제명
- Pathology
- 키워드
- Microfluidics
- 키워드
- Neutrophil
- 기타저자
- University of Colorado at Boulder Chemical and Biological Engineering
- 기본자료저록
- Dissertations Abstracts International. 87-02B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520260202104813
■006m o d
■007cr#unu||||||||
■020 ▼a9798291573334
■035 ▼a(MiAaPQ)AAI32167585
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.079
■1001 ▼aCalo, Christopher J.▼0(orcid)0009-0001-1262-107X
■24510▼aExtracellular Matrix Regulation of the Neutrophil Inflammatory Response
■260 ▼a[Sl]▼bUniversity of Colorado at Boulder▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a174 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-02, Section: B.
■500 ▼aAdvisor: Hind, Laurel E.
■5021 ▼aThesis (Ph.D.)--University of Colorado at Boulder, 2025.
■520 ▼aBacterial infections are a leading cause of death globally. This is due not only to the rising prevalence of antimicrobial resistance, but also because of the opportunistic nature of many bacteria allowing them to take advantage of people with diseases that compromise their immune systems, such as those afflicted with cancer, fibrosis, and cardiovascular diseases. Consequently, there is an urgent need to develop non-antibiotic treatments that will improve the survivability of bacterial infections. Targeting neutrophils poses an interesting avenue for therapeutic development as they are a major driver of the body's natural immune response to bacterial infections. In healthy individuals, neutrophils effectively trap and kill invading bacteria within hours of an infection occurring. However, dysregulated neutrophil function contributes to the pathogenesis of several diseases, leaving people susceptible to severe infections. Thus, targeting the neutrophil response to combat bacterial infections may greatly improve patient outcomes. To effectively design such therapeutics, it is imperative to understand the factors that regulate the neutrophil response. Interestingly, diseases associated with neutrophil dysregulation are often accompanied by changes to the extracellular matrix (ECM). While it is known that properties of the ECM regulate cell behavior, the extent to which aspects of the ECM affect the neutrophil response to bacteria remains incomplete. The ECM is a complex network of macromolecules making it difficult to study how specific aspects of the ECM affect neutrophil behavior.In this work, we employ a biologically inspired infection-on-a-chip microfluidic device to investigate how collagen concentration, enzymatic crosslinking of collagen, and the combination of various matrix proteins in the ECM affect elements of the neutrophil response to bacteria. We found that collagen concentration regulates neutrophil extravasation and migration in an endothelial cell-dependent manner. Additionally, lysyl oxidase, an enzyme that crosslinks collagen fibrils, decreased neutrophil extravasation but did not affect the migration patterns of extravasated neutrophils. This may be due to the enzyme inhibiting TGF-β1 signaling, a potent neutrophil chemoattractant. Lastly, we observed no difference in neutrophil extravasation into collagen matrices supplemented with fibronectin and laminin; however, the combinations of these proteins differentially regulated neutrophil migration in the ECM during the later hours of an infectious response.Together these data underscore the ECM as an active regulator of the neutrophil response and highlights the value of using physiologically relevant microfluidic systems for investigating intricate aspects of neutrophil biology that are traditionally inaccessible via simple in vitro systems and in vivo animal models. Further development of such tools will lead to a more complete understanding of neutrophil biology and ultimately intelligent therapeutic designs to correct neutrophil dysregulation.
■590 ▼aSchool code: 0051.
■650 4▼aImmunology
■650 4▼aPhysiology
■650 4▼aCellular biology
■650 4▼aPathology
■653 ▼aExtracellular matrix
■653 ▼aImmunoengineering
■653 ▼aInfection-on-a-chip
■653 ▼aMicrofluidics
■653 ▼aMicrophysiological systems
■653 ▼aNeutrophil
■690 ▼a0982
■690 ▼a0379
■690 ▼a0571
■690 ▼a0719
■71020▼aUniversity of Colorado at Boulder▼bChemical and Biological Engineering.
■7730 ▼tDissertations Abstracts International▼g87-02B.
■790 ▼a0051
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358943▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
