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Infectious and Hemorrhagic Hydrocephalus Share Molecular Mechanism Sensitive to Immune Modulation
Infectious and Hemorrhagic Hydrocephalus Share Molecular Mechanism Sensitive to Immune Modulation
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151112
- ISBN
- 9798382321677
- DDC
- 610
- 서명/저자
- Infectious and Hemorrhagic Hydrocephalus Share Molecular Mechanism Sensitive to Immune Modulation
- 발행사항
- [Sl] : Yale University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 96 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
- 주기사항
- Advisor: Diluna, Michael L.
- 학위논문주기
- Thesis (M.D.)--Yale University, 2024.
- 초록/해제
- 요약Hydrocephalus, characterized by a pathologic dilation of the brain's cerebrospinal fluid (CSF)-filled ventricles, may either be primary or acquired. Acquired hydrocephalus, most often caused by ventricular infection or hemorrhage, is currently treated by surgical CSF diversion with either a shunt or endoscopic third ventriculostomy - two procedures plagued by high failure and complication rates. The lack of pharmaceutical treatments is in part due to the obscure pathophysiology of the disease. We created novel rat models of post-infectious (PIH) and post-hemorrhagic hydrocephalus (PHH) and conducted a systems-level, multi-omics investigation of these animals to outline the cellular, molecular, and physiologic pathology of PIH and PHH, with the ultimate goal being to discover an effective pharmacological intervention.SPAK and toll like receptor 4 (TLR4) knockout (KO) rats were generated using Crispr/CAS9 genome editing. A catheter was implanted into the lateral ventricles of adult male rats; E. coli+/-LPS, LPS, autologous blood, or artificial CSF (aCSF) was administered over 48-72h. Ventricular size was determined either by volumetric analysis of serial images or MRI, and CSF secretion was measured by catheter placement into the lateral ventricle. Choroid plexus (ChP) was harvested for immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR) analysis, flow cytometry, genomic/proteomic examination, and single-cell RNA sequencing (scRNAseq). Additional proteins of interest were identified through liquid chromatography/dual mass spectroscopy (LC-MS/MS) analysis of purified protein complexes from digested ChP tissue; candidates were validated by WB/IHC. CSF cytokine analysis was performed by Eve Technologies.Intracerebroventricular (ICV) hemorrhage or infection with E. coli+LPS or LPS alone triggers a TLR4-dependent immune response at the ChP-CSF interface. The resulting CSF pro-inflammatory "cytokine storm", elicited from peripherally-derived and border-associated ChP macrophages, caused an increase in CSF production from the ChP epithelium via phospho-activation of the tumor necrosis factor (TNF) receptor-associated kinase SPAK, which acts as regulatory scaffold for a multi-ion transporter protein complex comprised of the NKCC1, the alpha-1 subunit of the Na/K ATPase, KCNJ13, CLIC6, WNK1, and AQP1. Genetic KO of TLR4 or SPAK in rats, as well as pharmacological immunosuppression with rapamycin, prevents PIH and PHH by antagonizing the ChP inflammation that causes SPAK-dependent CSF hypersecretion.These results expand our understanding of ChP immune-epithelial cell crosstalk and reframe PIH and PHH, which are historically known as diseases of impaired CSF flow through the ventricular system, as related neuroinflammatory disorders sensitive to immunomodulation. Such findings may reduce the need for invasive, surgical CSF diversion procedures.
- 일반주제명
- Medicine
- 일반주제명
- Health sciences
- 일반주제명
- Neurosciences
- 키워드
- Hydrocephalus
- 키워드
- Choroid plexus
- 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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■00520250211151112
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■020 ▼a9798382321677
■035 ▼a(MiAaPQ)AAI31144447
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a610
■1001 ▼aReeves, Benjamin C.
■24510▼aInfectious and Hemorrhagic Hydrocephalus Share Molecular Mechanism Sensitive to Immune Modulation
■260 ▼a[Sl]▼bYale University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a96 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-11, Section: B.
■500 ▼aAdvisor: Diluna, Michael L.
■5021 ▼aThesis (M.D.)--Yale University, 2024.
■520 ▼aHydrocephalus, characterized by a pathologic dilation of the brain's cerebrospinal fluid (CSF)-filled ventricles, may either be primary or acquired. Acquired hydrocephalus, most often caused by ventricular infection or hemorrhage, is currently treated by surgical CSF diversion with either a shunt or endoscopic third ventriculostomy - two procedures plagued by high failure and complication rates. The lack of pharmaceutical treatments is in part due to the obscure pathophysiology of the disease. We created novel rat models of post-infectious (PIH) and post-hemorrhagic hydrocephalus (PHH) and conducted a systems-level, multi-omics investigation of these animals to outline the cellular, molecular, and physiologic pathology of PIH and PHH, with the ultimate goal being to discover an effective pharmacological intervention.SPAK and toll like receptor 4 (TLR4) knockout (KO) rats were generated using Crispr/CAS9 genome editing. A catheter was implanted into the lateral ventricles of adult male rats; E. coli+/-LPS, LPS, autologous blood, or artificial CSF (aCSF) was administered over 48-72h. Ventricular size was determined either by volumetric analysis of serial images or MRI, and CSF secretion was measured by catheter placement into the lateral ventricle. Choroid plexus (ChP) was harvested for immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR) analysis, flow cytometry, genomic/proteomic examination, and single-cell RNA sequencing (scRNAseq). Additional proteins of interest were identified through liquid chromatography/dual mass spectroscopy (LC-MS/MS) analysis of purified protein complexes from digested ChP tissue; candidates were validated by WB/IHC. CSF cytokine analysis was performed by Eve Technologies.Intracerebroventricular (ICV) hemorrhage or infection with E. coli+LPS or LPS alone triggers a TLR4-dependent immune response at the ChP-CSF interface. The resulting CSF pro-inflammatory "cytokine storm", elicited from peripherally-derived and border-associated ChP macrophages, caused an increase in CSF production from the ChP epithelium via phospho-activation of the tumor necrosis factor (TNF) receptor-associated kinase SPAK, which acts as regulatory scaffold for a multi-ion transporter protein complex comprised of the NKCC1, the alpha-1 subunit of the Na/K ATPase, KCNJ13, CLIC6, WNK1, and AQP1. Genetic KO of TLR4 or SPAK in rats, as well as pharmacological immunosuppression with rapamycin, prevents PIH and PHH by antagonizing the ChP inflammation that causes SPAK-dependent CSF hypersecretion.These results expand our understanding of ChP immune-epithelial cell crosstalk and reframe PIH and PHH, which are historically known as diseases of impaired CSF flow through the ventricular system, as related neuroinflammatory disorders sensitive to immunomodulation. Such findings may reduce the need for invasive, surgical CSF diversion procedures.
■590 ▼aSchool code: 0265.
■650 4▼aMedicine
■650 4▼aHealth sciences
■650 4▼aNeurosciences
■653 ▼aHydrocephalus
■653 ▼aPost-hemorrhagic hydrocephalus
■653 ▼aImmune modulation
■653 ▼aPharmacological intervention
■653 ▼aChoroid plexus
■690 ▼a0564
■690 ▼a0566
■690 ▼a0317
■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=T17160757▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
