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与显著的发病率和死亡率相关，可用的治疗选择仅有限 功效巨噬细胞被认为在SSc皮肤病的发病机制中发挥重要作用， 它们可以在促炎症和促纤维化/损伤消退之间改变其表型。此外，最近 高通量分子技术的进展，分析了SSc的全组织皮肤活检， 患者提示巨噬细胞是SSc中重要的细胞靶点，但巨噬细胞的确切作用 在SSc真皮纤维化中的作用尚不清楚。我们将利用尖端技术， 多参数流式细胞术分离皮肤巨噬细胞及其基因分析 使用RNAseq的表达谱。皮肤活组织检查将从健康对照受试者和从健康对照受试者获得。 与SSc患者，以确定SSc特异性真皮巨噬细胞签名。我们还将获得皮肤活检 从SSc患者之前和之后霉酚酸酯（MMF）治疗，并比较签名之间 与未治疗的患者相比，治疗应答者和无应答者。这些研究是及时的，因为 来自第一个随机双盲临床研究的最新数据表明，MMF是治疗SSc的有效药物 皮肤病我们假设巨噬细胞是SSc皮肤病患者的潜在治疗靶点， 疾病，从拟议的研究中获得的新知识将阐明 巨噬细胞在SSc的真皮纤维化中起作用。这些研究虽然风险很高，但回报也很高 信息有可能是范式转移，是理想的R21赠款机制。 !