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Nucleolar Stress and Il-1 Signaling in Hematopoietic Stem Cell Aging
Nucleolar Stress and Il-1 Signaling in Hematopoietic Stem Cell Aging
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152008
- ISBN
- 9798383046432
- DDC
- 574
- 서명/저자
- Nucleolar Stress and Il-1 Signaling in Hematopoietic Stem Cell Aging
- 발행사항
- [Sl] : Columbia University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 225 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
- 주기사항
- Advisor: Passegue, Emmanuelle.
- 학위논문주기
- Thesis (Ph.D.)--Columbia University, 2024.
- 초록/해제
- 요약The aging of the hematopoietic system is driven in part by defects occurring in hematopoietic stem cells (HSC). Given that HSCs provide the organism with blood and immune cells lifelong, understanding the mechanisms underlying HSC aging is vital to develop interventions that address the deterioration of the hematopoietic system at its root. Past work has indicated roles for both intrinsic and extrinsic processes in driving HSC decline during aging. Still, their roles are not fully understood, especially the relationship between different drivers, and the mechanisms by which HSCs maintain functionality in the face of age-related insults. To better understand cell-intrinsic regulation of HSC aging, we investigated nucleolar DNA damage marks stemming from replication stress in old HSCs, and connected it with nucleolar stress induction which impairs protein translation and cell cycling. Although nucleolar stress dampens old HSC activity, we reveal the cytoprotective effect of the p53-mediated nucleolar stress response to be essential for preserving the residual potential of old HSCs. Additionally, though inflammation from the niche contributes to HSC aging, the exact role of microenvironmental alterations often remains unclear. Here, we uncover an important role for IL-1 derived from endosteal stromal cells in driving both HSC and niche cell aging, and demonstrate inhibition of IL-1 signaling as a tractable strategy that counters niche deterioration to improve HSC function. These findings unveil new mechanisms of HSC aging, raise the possibility that nucleolar stress signaling could be harnessed to improve the output of old HSCs in clinical settings, and demonstrate the therapeutic viability of IL-1 blockade in improving old HSC function.
- 일반주제명
- Cellular biology
- 일반주제명
- Molecular biology
- 일반주제명
- Aging
- 키워드
- DNA damage
- 키워드
- Hematopoiesis
- 키워드
- Inflammation
- 키워드
- Nucleolar stress
- 기타저자
- Columbia University Cellular Molecular and Biomedical Studies
- 기본자료저록
- Dissertations Abstracts International. 85-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211152008
■006m o d
■007cr#unu||||||||
■020 ▼a9798383046432
■035 ▼a(MiAaPQ)AAI31330883
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aMitchell, Carl Abbate.
■24510▼aNucleolar Stress and Il-1 Signaling in Hematopoietic Stem Cell Aging
■260 ▼a[Sl]▼bColumbia University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a225 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-12, Section: B.
■500 ▼aAdvisor: Passegue, Emmanuelle.
■5021 ▼aThesis (Ph.D.)--Columbia University, 2024.
■520 ▼aThe aging of the hematopoietic system is driven in part by defects occurring in hematopoietic stem cells (HSC). Given that HSCs provide the organism with blood and immune cells lifelong, understanding the mechanisms underlying HSC aging is vital to develop interventions that address the deterioration of the hematopoietic system at its root. Past work has indicated roles for both intrinsic and extrinsic processes in driving HSC decline during aging. Still, their roles are not fully understood, especially the relationship between different drivers, and the mechanisms by which HSCs maintain functionality in the face of age-related insults. To better understand cell-intrinsic regulation of HSC aging, we investigated nucleolar DNA damage marks stemming from replication stress in old HSCs, and connected it with nucleolar stress induction which impairs protein translation and cell cycling. Although nucleolar stress dampens old HSC activity, we reveal the cytoprotective effect of the p53-mediated nucleolar stress response to be essential for preserving the residual potential of old HSCs. Additionally, though inflammation from the niche contributes to HSC aging, the exact role of microenvironmental alterations often remains unclear. Here, we uncover an important role for IL-1 derived from endosteal stromal cells in driving both HSC and niche cell aging, and demonstrate inhibition of IL-1 signaling as a tractable strategy that counters niche deterioration to improve HSC function. These findings unveil new mechanisms of HSC aging, raise the possibility that nucleolar stress signaling could be harnessed to improve the output of old HSCs in clinical settings, and demonstrate the therapeutic viability of IL-1 blockade in improving old HSC function.
■590 ▼aSchool code: 0054.
■650 4▼aCellular biology
■650 4▼aMolecular biology
■650 4▼aAging
■653 ▼aDNA damage
■653 ▼aHematopoiesis
■653 ▼aHematopoietic stem cells
■653 ▼aInflammation
■653 ▼aNucleolar stress
■690 ▼a0379
■690 ▼a0307
■690 ▼a0493
■71020▼aColumbia University▼bCellular, Molecular and Biomedical Studies.
■7730 ▼tDissertations Abstracts International▼g85-12B.
■790 ▼a0054
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17162402▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
