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Multi-Omic Characterization of Macrophage Activation States in Systemic Sclerosis
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Multi-Omic Characterization of Macrophage Activation States in Systemic Sclerosis. |
| 개인저자 | Toledo, Diana M. |
| 단체저자명 | Dartmouth College. Genetics. |
| 발행사항 | [S.l.]: Dartmouth College., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 224 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-04B. Dissertation Abstract International |
| ISBN | 9781085747097 |
| 학위논문주기 | Thesis (Ph.D.)--Dartmouth College, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-04, Section: B.
Advisor: Whitfield, Michael L. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by fibrosis of the skin and internal organs. Alternatively-activated/pro-fibrotic macrophages (M2) have been implicated in SSc pathogenesis and may be a key cell type driving fibrosis. The precise phenotype of the macrophages in SSc tissues has not been well defined. There are currently no FDA-approved therapies for patients with SSc, though many recently tested drugs that show clinical benefit modulate macrophage activation and recruitment. In this dissertation, I have used multiple approaches to test the hypothesis that macrophages from patients with SSc are alternatively-activated and used a novel three-dimensional skin-like tissue to show that SSc macrophages increase tissue thickness and stiffness when cultured with patient fibroblasts and plasma. I took a multi-omic approach and used a combination of techniques to answer my scientific questions. I assessed the transcriptome and examined the epigenetic state of cells and tissues by analyzing DNA methylation and chromatin accessibility, all on a genome-wide scale. In Chapter 2, I demonstrate that mycophenolate mofetil (MMF) treatment modulates monocytes, macrophages, and dendritic cells (myeloid-lineage) in vivo. Continuous MMF treatment causes decreases in CCL2 (monocyte chemoattractant) expression and decreases CD163-positive macrophages in the skin of patients with SSc. In Chapter 3, I show that adding this key cell type into 3D skin-like tissues using SSc-derived dermal fibroblasts results in tissue activation that more closely resemble the SSc molecular pathways seen in skin, allowing for an optimized in vitro model system of SSc. In Chapter 4, I characterize the macrophage subtypes of six different macrophage activation states, including SSc-like/fibrotic macrophages, using DNA methylation. I can use this powerful data to accurately deconvolute the macrophage subtype proportions in SSc tissue. These projects summarize advanced in an in vitro 3D tissue model system of SSc for pre-clinical screening of potential drug candidates and the identification of patients who have a high proportion of dysregulated/pro-fibrotic macrophages. This system can serve as a tool to identify individuals with an increased likelihood of responding to therapies that target macrophages, with the ultimate goal of developing better therapeutics that acquire FDA-approval for the treatment of SSc. |
| 일반주제명 | Genetics. Immunology. Systems science. |
| 언어 | 영어 |
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: 이 자료의 원문은 한국교육학술정보원에서 제공합니다. |
