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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林建達 | zh_TW |
| dc.contributor.advisor | Jian-Da Lin | en |
| dc.contributor.author | 連家瑢 | zh_TW |
| dc.contributor.author | Chia-Jung Lien | en |
| dc.date.accessioned | 2024-08-23T16:17:44Z | - |
| dc.date.available | 2024-08-24 | - |
| dc.date.copyright | 2024-08-23 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-08-05 | - |
| dc.identifier.citation | [1] Shutong Du, Hyunju Kim, and Casey M Rebholz. Higher ultra-processed food consumption is associated with increased risk of incident coronary artery disease in the atherosclerosis risk in communities study, 2021.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/94986 | - |
| dc.description.abstract | 動脈粥樣硬化的進展和退行性變化與1 型和2 型免疫反應密切相關。先前研究表明，蠕蟲感染，如鞭蟲（Trichuris muris）和多角螺旋蟲（Heligmosomoides polygyrus），可誘導2型免疫反應和調節性T細胞（Tregs）的擴展，影響腸道微生物組。本研究探討蠕蟲誘導的2 型免疫對動脈粥樣硬化的緩解作用，著重研究C57BL/6小鼠（包括WT和Nod2-/-基因型）中腸道微生物群與免疫細胞亞群在主動脈弓和腸固有層的相互作用。通過16S rRNA 測序和光譜流式細胞術及CITE-seq，我們發現與疾病狀態相關的顯著微生物群變化。動脈粥樣硬化的進展與Blautia和Faecalibaculum的增加相關，而退行性變化則與產生丁酸鹽的菌屬如Butyricicoccus和Eubacterium Nodaum Group相關。免疫反應的變化包括某些巨噬細胞亞群的減少和主動脈弓中Th2細胞的增加，以及退行性變化期間腸固有層中Tregs細胞的增加。我們應用CITE-Seq分析了主動脈弓和腸固有層中免疫細胞群
的變化，探討了這些特定細胞群如何影響動脈粥樣硬化及其逆轉途徑。研究結果表明，微生物群與免疫的相互作用在動脈粥樣硬化的進展和退行中起關鍵作用，突顯了微生物群作為疾病階段生物標誌物的潛力，並提供了新療法的見解。 | zh_TW |
| dc.description.abstract | Atherosclerosis progression and regression have been previously linked to type 1and type 2 immune responses. Prior studies have demonstrated that helminth infections,specifically with Trichuris muris (T. muris) and Heligmosomoides polygyrus (H. poly), can
induce strong type 2 immune responses and the expansion of regulatory T cells (Tregs),further influencing the composition of the gut microbiome. Our study explored the effectsof helminth-induced type 2 immunity in atherosclerosis, focusing on the interplay between gut microbiota and immune cell subsets in the aortic arch and gut lamina propria lymphocytesof C57BL/6 mice, including both WT and Nod2-/- genotypes. Through longitudinal microbiome survey via 16S rRNA sequencing and immune profiling with spectral flow cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), we identified significant microbiota alterations associated with disease states. Atherosclerosis progression correlated with genus increases in Blautia and Dubosiella, whereas regression was associated with butyrate-producing genera such as Butyricicoccus. Changes in immune response included a reduction in certain macrophage subsets and an increase in Th2 cells in the aortic arch, alongside an increase in Treg cells in the lamina propria during helminth-indued aortic plaque regression. We applied CITE-seq to map immune population shifts in the aortic arch and lamina propria to further acquire transcriptomic changes in atherosclerosis. We explored how these specific clusters affect atherosclerosis and their pathways to disease reversing. Our findings suggest a pivotal role of microbiome-immune interactions in atherosclerosis progression and helminth-induced aortic plaque regression, highlighting the microbiome’s potential as a biomarker for disease stages and providing insights into novel therapeutic strategies. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-23T16:17:39Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-23T16:17:44Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | Verification Letter from the Oral Examination Committee i
Acknowledgements iii 摘要v Abstract vii Contents ix List of Figures xv List of Tables xix Denotation xxi Chapter 1 Introduction 1 1.1 Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 The Role of Monocytes and Macrophages . . . . . . . . . . . . . . . 3 1.3 Type 1 and Type 2 Immune Responses in Atherosclerosis . . . . . . . 4 1.4 Heligmosomoides polygyrus and Trichuris muris Infection . . . . . . 6 1.5 Gut-Heart Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Chapter 2 Materials and Methods 9 2.1 Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 2.1.1 Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 2.1.2 Immune Populations . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.1.3 TotalSeq™-A Mouse Universal Cocktail . . . . . . . . . . . . . . . 14 2.1.4 Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.1.5 Equipment and Apparatus . . . . . . . . . . . . . . . . . . . . . . . 20 2.1.6 Analysis Packages Used in the Study . . . . . . . . . . . . . . . . . 21 2.2 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.3 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.3.1 Cultivation and Infection of Heligmosomoides Polygyrus . . . . . . 23 2.3.2 Cultivation and Infection of Trichuris muris . . . . . . . . . . . . . 24 2.3.3 Enumeration of H. polygyrus and T. muris Eggs in Fecal Sample . . 25 2.3.4 Frozen Section Biopsy of Aortic Roots . . . . . . . . . . . . . . . . 25 2.3.5 Oil Red-O Staining of Aortic Plaques . . . . . . . . . . . . . . . . 26 2.3.6 Isolation of Cells from Tissues . . . . . . . . . . . . . . . . . . . . 26 2.3.6.1 Isolation of Lamina Propria Lymphocytes . . . . . . . 26 2.3.6.2 Isolation of Aortic Arch Cells . . . . . . . . . . . . . . 27 2.3.7 Measurement of Plasma Cholesterol Concentration . . . . . . . . . 28 2.3.8 Proinflammatory and Th1/Th2 Cytokine Measurement . . . . . . . 28 2.3.9 Flow Cytometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.3.9.1 Lamina Propria Lymphocytes Staining . . . . . . . . . 30 2.3.9.2 Aortic Arch Cells Staining . . . . . . . . . . . . . . . 30 2.3.9.3 Flow Cytometry Analysis of Multiple Cell Types . . . 31 2.3.10 Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-Seq) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 2.3.10.1 CD45+ Cells Sorting for TotalSeq-A and Hash-Tag Antibody Preparation . . . . . . . . . . . . . . . . . . . . 33 2.3.10.2 TotalSeq-A and HashTag Antibody Preparation . . . . 33 2.3.10.3 Cells staining of TotalSeq-A and Hash-Tag Antibody . 34 2.3.10.4 10x Genomics Library Preparation for CITE-Seq . . . . 34 2.3.10.5 CITE-seq Data Analysis . . . . . . . . . . . . . . . . . 35 2.3.11 Cell-Cell Communication Analysis with CellChat . . . . . . . . . . 35 2.3.12 Exploring Microbiome-Immune Associations via sPLS Analysis . . 36 2.3.13 Statistical Analysis of Group Differences in This Study . . . . . . . 37 Chapter 3 Results 39 3.1 Atherosclerotic Development During the Progression Stage . . . . . 39 3.1.1 AAV-mPCSK9 Injection Mediated Hypercholesterolemia in Vivo . . 39 3.1.2 Weight Gain During the Progression Stage . . . . . . . . . . . . . . 40 3.1.3 Plaque Formation under Atherosclerotic Induction . . . . . . . . . . 40 3.2 Helminth-Induced Regression of Atherosclerosis . . . . . . . . . . . 41 3.2.1 Confirmation of Successful H.poly Infection in Mice . . . . . . . . 41 3.2.2 Verified Successful Infection of T. muris in Mice . . . . . . . . . . 42 3.2.3 Reduction in Body Weight and Cholesterol Levels . . . . . . . . . . 42 3.2.4 Reduced Plaque Area Under Helminth-Induced Regression . . . . . 43 3.3 Induction of Type 2 Immunity by Helminth Infection . . . . . . . . . 43 3.3.1 Cytokines in Peripheral Plasma Indicate Regression of Atherosclerosis 44 3.3.2 Type 2 Immunity Observed in Peripheral Blood Immune Populations 44 3.3.3 Enhancement of Type 2 Immunity and Macrophage Differentiation in the Aortic Arch During Helminth-Induced Regression . . . . . . 45 3.3.3.1 Decrease of Ly6C+ Monocytes During the Regression Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 3.3.3.2 Significant Reduction and Polarization Shift in Macrophages During the Regression Stage . . . . . . . . . . . . . . 45 3.3.4 Type 2 Immunity and Immune Regulation Induced in Lamina Propria by Helminth Infection During Regression . . . . . . . . . . . . 46 3.3.4.1 Treg Subsets Across Different Disease Stages in LPL . 46 3.3.4.2 Decreased Naïve CD4+ T Cells in T. muris Infection Regression Group . . . . . . . . . . . . . . . . . . . . 47 3.4 Single-cell Analysis Reveals Transcriptomic Differences in Different Stages of the Aortic Arch . . . . . . . . . . . . . . . . . . . . . . . . 48 3.4.1 Cell-Cell Interaction in Aortic Arch is More Active in Nod2-/- Mice . 48 3.4.2 Decreased Macrophage Proportions During the Regression Stages in Both Genotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 3.4.2.1 Identification of Macrophages with Pro-Inflammatory Phenotypes in Progression Stages . . . . . . . . . . . . 50 3.4.2.2 Macrophages Tend to Exhibit Greater Tissue Repair Ability During the Regression Stage . . . . . . . . . . . . . 51 3.4.2.3 Plaque Instability in Nod2-/- Mice Revealed by DESeq Analysis . . . . . . . . . . . . . . . . . . . . . . . . . 53 3.4.3 B Cell Contribution in the Aortic Arch Under Atherosclerosis . . . . 55 3.4.3.1 Identification of B Cell Subsets Under Different Disease Stages . . . . . . . . . . . . . . . . . . . . . . . . 55 3.4.3.2 Functional Analysis Reveals the Role of B Cells in the Aortic Arch . . . . . . . . . . . . . . . . . . . . . . . 56 3.4.4 Proportion of T Cells in the Aortic Arch During Atherosclerosis . . 57 3.4.4.1 Reduction of Type 1 Immunity During the Regression Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 3.4.4.2 Type 2 Immunity and Regulatory Function Induced by Helminth Infection in WT Mice . . . . . . . . . . . . . 58 3.4.4.3 Th17 Cells Increase in Nod2-/- Mice During the Regression Stage . . . . . . . . . . . . . . . . . . . . . . . . 59 3.5 Single-Cell Analysis Reveals Transcriptomic Variations Across Different Stages in Lamina Propria . . . . . . . . . . . . . . . . . . . . 59 3.5.1 Cell-Cell Interactions in LP are More Active in Nod2-/- Mice During the Regression Stage . . . . . . . . . . . . . . . . . . . . . . . . . 60 3.5.2 Increased Contributions of Macrophages During the Regression Stage in Both Genotypes . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3.5.2.1 Resident-like and Trem2Hi Macrophages Increase Inflammation in Nod2-/- Mice During the Regression Stage 60 3.5.2.2 Fibrotic Macrophages May Exhibit Tissue Repair in WT Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 3.5.3 Identification of Type 2 Immunity Induction Through T Cells in LP 62 3.5.3.1 Successful Induction of Type 2 Immunity in WT Mice During the Regression Stage . . . . . . . . . . . . . . 62 3.5.3.2 Inflammation Increases in Nod2-/- Mice Due to Helminth Infection During the Regression Stage . . . . . . . . . 63 3.6 Correlational Analysis of Microbiome and Immune Cell Populations with Immune Populations . . . . . . . . . . . . . . . . . . . . . . . 64 3.6.1 Identification of Disease Stage-Specific Microbiome Using LEfSe Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 3.6.2 Association Between Microbiome and Immune Cell Populations in the Aortic Arch . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Chapter 4 Discussion 97 4.1 Differentiating the Effects of Helminth Infection and Dietary Changes on Gut Microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 4.2 Potential Therapeutic Implications of Helminth-Derived ES Proteins in Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Chapter 5 Conclusion 99 References 101 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 動脈粥狀硬化 | zh_TW |
| dc.subject | 第二型免疫反應 | zh_TW |
| dc.subject | 微生物 | zh_TW |
| dc.subject | 寄生蟲 | zh_TW |
| dc.subject | 腸心軸 | zh_TW |
| dc.subject | Atherosclerosis | en |
| dc.subject | Gut-Heart Axis | en |
| dc.subject | Microbiome | en |
| dc.subject | Type 2 Immunity | en |
| dc.subject | Helminth | en |
| dc.title | 探討腸心軸於蠕蟲感染促動脈粥狀硬化消退之作用 | zh_TW |
| dc.title | Interrogate the Gut-Heart Axis in Helminth-induced Aortic Plaque Regression during Atherosclerosis | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 阮雪芬;許家郎;黃宣誠;陳倩瑜 | zh_TW |
| dc.contributor.oralexamcommittee | Hsueh-Fen Juan;Chia-Lang Hsu;Hsuan-Cheng Huang;Chien-Yu Chen | en |
| dc.subject.keyword | 動脈粥狀硬化,腸心軸,微生物,第二型免疫反應,寄生蟲, | zh_TW |
| dc.subject.keyword | Atherosclerosis,Gut-Heart Axis,Microbiome,Type 2 Immunity,Helminth, | en |
| dc.relation.page | 114 | - |
| dc.identifier.doi | 10.6342/NTU202402568 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2024-08-08 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科技學系 | - |
| dc.date.embargo-lift | 2029-07-29 | - |
| 顯示於系所單位： | 生化科技學系 | |
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