Transcriptional Signature of Macrophages in SSc

SSc 中巨噬细胞的转录特征

• 批准号: 10005890
• 负责人: Harris R Perlman
• 金额: $ 17.38万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005890
• 关键词: Affect; Bilateral; Biology; Biopsy; Case Fatality Rates; Cellcept; Cells; Clinical; Clinical Research; Collaborations; Complex; Cross-Sectional Studies; Data; Dermal; Development; Disease; Double-Blind Method; Drug Targeting; Enrollment; Fibrosis; Flow Cytometry; Forearm; Frequencies; Future; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; Goals; Gold; Grant; Immunohistochemistry; Immunomodulators; Inflammation; Inflammatory; Injury; Knowledge; Light; Lung; Lung diseases; Lymphocyte; Meta-Analysis; Molecular; Morbidity - disease rate; Mycophenolate; Nature; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Population; Protocols documentation; Publications; Randomized; Research Personnel; Resolution; Rheumatism; Role; Scleroderma; Series; Skin; Skin Tissue; Systemic Scleroderma; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Trichrome stain; Work; base; biomedical referral center; cell type; cellular targeting; cohort; effective therapy; experimental study; high reward; high risk; histological studies; macrophage; monocyte; mortality; mycophenolate mofetil; new therapeutic target; next generation sequencing; novel; novel strategies; peripheral blood; programs; prospective; recruit; responders and non-responders; response; skin disorder; skin fibrosis; tertiary care; transcriptome; transcriptome sequencing; transcriptomics; treatment responders; treatment response

SSc is associated with significant morbidity and mortality and available therapeutic options have only limited efficacy. Macrophages are thought to play a major role in the pathogenesis of SSc dermal disease because they can alter their phenotype between pro-inflammation and pro-fibrosis/injury resolution. Additionally, recent advances in high-throughput molecular technologies that analyzed whole tissue skin biopsies from SSc patients suggest that macrophages are important cellular targets in SSc, but the precise role macrophages play in SSc dermal fibrosis is unknown. We will take advantage of cutting edge technology that will allow for isolation of macrophages from skin biopsies using multi-parameter flow cytometry and analyze their gene expression profile using RNAseq. Skin biopsies will be obtained from healthy control subjects and from patients with SSc to identify the SSc-specific dermal macrophage signature. We will also obtain skin biopsies from SSc patients before and post mycophenolate mofetil (MMF) treatment and compare signatures between treatment responders and non-responders compared to untreated patients. These studies are timely because recent data from the first randomized double-blinded clinical study suggest that MMF is a useful agent for SSc skin disease. We hypothesize that macrophages are a potential treatment target for patients with SSc dermal disease, and that the new knowledge gained from the proposed studies will shed light upon the role that macrophages play in dermal fibrosis in SSc. These studies, while high-risk, will generate high reward information that has the potential be to paradigm shifting and is ideal for the R21 grant mechanism. !

SSC与显着的发病率和死亡率有关，可用的治疗选择只有限制 功效。人们认为巨噬细胞在SSC真皮疾病的发病机理中起主要作用，因为 他们可以在促炎和纤维化/损伤分辨率之间改变表型。另外，最近 高通量分子技术的进步，分析了SSC的整个组织皮肤活检 患者认为巨噬细胞是SSC中重要的细胞靶标，但精确的作用巨噬细胞 在SSC真皮纤维化中发挥作用是未知的。我们将利用最先进的技术 使用多参数流式细胞仪从皮肤活检中分离巨噬细胞并分析其基因 使用RNASEQ的表达曲线。皮肤活检将从健康的对照对象和 SSC患者以鉴定SSC特异性皮肤巨噬细胞特征。我们还将获得皮肤活检 从SSC患者和霉酚酸酯（MMF）治疗后的SSC患者中进行比较 与未经治疗的患者相比，治疗响应者和无反应者。这些研究是及时的，因为 第一个随机双盲临床研究的最新数据表明，MMF是SSC的有用药物 皮肤病。我们假设巨噬细胞是SSC真皮患者的潜在治疗靶 疾病，从拟议的研究中获得的新知识将揭示 巨噬细胞在SSC的真皮纤维化中发挥作用。这些研究虽然高风险将产生高奖励 潜在的信息是范式转移，是R21赠款机制的理想选择。 呢