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The Choroid Plexus Links Innate Immunity to Dysregulation of CSF Homeostasis in Diverse Forms of Hydrocephalus
The Choroid Plexus Links Innate Immunity to Dysregulation of CSF Homeostasis in Diverse Forms of Hydrocephalus
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151126
- ISBN
- 9798382321585
- DDC
- 610
- 저자명
- Kiziltug, Emre.
- 서명/저자
- The Choroid Plexus Links Innate Immunity to Dysregulation of CSF Homeostasis in Diverse Forms of Hydrocephalus
- 발행사항
- [Sl] : Yale University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 100 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
- 주기사항
- Advisor: Herzog, Erica.
- 학위논문주기
- Thesis (M.D.)--Yale University, 2024.
- 초록/해제
- 요약The choroid plexus (ChP) secretes a half-liter/day of cerebrospinal fluid (CSF) and is the blood-CSF barrier with critical immune functions. Hydrocephalus, commonly caused by infection or hemorrhage, lacks non-surgical treatments due to obscure pathobiology. We hypothesize that in acquired hydrocephalus, the dual ChP functions of CSF secretion and blood-CSF barrier maintenance become pathologically entangled in a maladaptive disease state. To test this hypothesis, we created novel rat models of post-infectious (PIH) and posthemorrhagic hydrocephalus (PHH) and conducted a multi-omics investigation of these animals to dissect the cellular, molecular, and physiological pathology underlying PIH and PHH . Our systems approach combined functional genomics to characterize the ChP immune response, including the first-ever single-cell transcriptomic profile of the ChP in a pathological condition, as well as in vivo assessments of ChP secretory capacity and CSF dynamics to systematically characterize fluid homeostasis. Integrated multi-omic analysis of diverse post-infectious (PIH) and post-hemorrhagic (PHH) hydrocephalus models show lipopolysaccharide and blood products, respectively, trigger highly similar Tlr4-dependent immune-secretory responses at the ChP-CSF interface. Activated ChP macrophages elicit a CSF "cytokine storm" that stimulates CSF production from ChP epithelial cells via a kinase-regulated multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents acute PIH and PHH by antagonizing ChP-mediated CSF hypersecretion. These data expand our understanding of ChP immune-epithelial cell crosstalk, reframe PIH and PHH as related neuroinflammatory disorders, and identify a druggable target of ChP immune-secretory function.
- 일반주제명
- Medicine
- 일반주제명
- Neurosciences
- 일반주제명
- Bioinformatics
- 일반주제명
- Health sciences
- 키워드
- Choroid plexus
- 키워드
- Hydrocephalus
- 기타저자
- Yale University Yale School of Medicine
- 기본자료저록
- Dissertations Abstracts International. 85-11B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211151126
■006m o d
■007cr#unu||||||||
■020 ▼a9798382321585
■035 ▼a(MiAaPQ)AAI31147020
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a610
■1001 ▼aKiziltug, Emre.
■24510▼aThe Choroid Plexus Links Innate Immunity to Dysregulation of CSF Homeostasis in Diverse Forms of Hydrocephalus
■260 ▼a[Sl]▼bYale University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a100 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-11, Section: B.
■500 ▼aAdvisor: Herzog, Erica.
■5021 ▼aThesis (M.D.)--Yale University, 2024.
■520 ▼aThe choroid plexus (ChP) secretes a half-liter/day of cerebrospinal fluid (CSF) and is the blood-CSF barrier with critical immune functions. Hydrocephalus, commonly caused by infection or hemorrhage, lacks non-surgical treatments due to obscure pathobiology. We hypothesize that in acquired hydrocephalus, the dual ChP functions of CSF secretion and blood-CSF barrier maintenance become pathologically entangled in a maladaptive disease state. To test this hypothesis, we created novel rat models of post-infectious (PIH) and posthemorrhagic hydrocephalus (PHH) and conducted a multi-omics investigation of these animals to dissect the cellular, molecular, and physiological pathology underlying PIH and PHH . Our systems approach combined functional genomics to characterize the ChP immune response, including the first-ever single-cell transcriptomic profile of the ChP in a pathological condition, as well as in vivo assessments of ChP secretory capacity and CSF dynamics to systematically characterize fluid homeostasis. Integrated multi-omic analysis of diverse post-infectious (PIH) and post-hemorrhagic (PHH) hydrocephalus models show lipopolysaccharide and blood products, respectively, trigger highly similar Tlr4-dependent immune-secretory responses at the ChP-CSF interface. Activated ChP macrophages elicit a CSF "cytokine storm" that stimulates CSF production from ChP epithelial cells via a kinase-regulated multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents acute PIH and PHH by antagonizing ChP-mediated CSF hypersecretion. These data expand our understanding of ChP immune-epithelial cell crosstalk, reframe PIH and PHH as related neuroinflammatory disorders, and identify a druggable target of ChP immune-secretory function.
■590 ▼aSchool code: 0265.
■650 4▼aMedicine
■650 4▼aNeurosciences
■650 4▼aBioinformatics
■650 4▼aHealth sciences
■653 ▼aChoroid plexus
■653 ▼aHydrocephalus
■653 ▼aIntegrative genomics
■653 ▼aCerebrospinal fluid
■653 ▼aPharmacological immunomodulation
■690 ▼a0564
■690 ▼a0317
■690 ▼a0715
■690 ▼a0566
■71020▼aYale University▼bYale School of Medicine.
■7730 ▼tDissertations Abstracts International▼g85-11B.
■790 ▼a0265
■791 ▼aM.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17160851▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
