Understanding transcriptional connections between cutaneous and systemic lupus

了解皮肤狼疮和系统性狼疮之间的转录联系

• 批准号: 8825016
• 负责人: Joanne Michelle Kahlenberg
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825016
• 关键词: Affect; American; Archives; Autoantibodies; Autoimmune Diseases; Biological; Biological Markers; Biopsy; Biopsy Specimen; Cicatrix; Classification; Clinical; Clinical Data; Complementary DNA; Computer software; Creatinine; Cutaneous; Cutaneous Lupus Erythematosus; Dermal; Development; Diagnosis; Disease; Disease Outcome; Disease Pathway; Down-Regulation; Environmental Exposure; European; Exanthema; Flare; Formalin; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Expression Regulation; Gene-Modified; Graph; Histologic; Immune system; Immunohistochemistry; Inflammation; Inflammatory; Kidney; Knowledge; Lesion; Life; Lupus; Lupus Nephritis; Methods; Michigan; Microarray Analysis; Molecular; Molecular Profiling; Monitor; Morbidity - disease rate; Nephritis; Organ; Outcome; Paraffin Embedding; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Patients; Population; Prevention; Prevention strategy; Proteinuria; Public Health; Quality of life; RNA; Research; Research Design; Research Project Grants; Rheumatology; Risk; Serum; Skin; Survival Analysis; Systemic Lupus Erythematosus; Systemic disease; Systems Biology; Time; Tissue Sample; Tissues; Ultraviolet Rays; Universities; base; cardiovascular disorder risk; clinical phenotype; college; disorder prevention; disorder risk; disorder subtype; genome-wide; improved; indexing; information gathering; interest; lupus cutaneous; new therapeutic target; novel; public health relevance; skin disorder; tool; treatment strategy

 DESCRIPTION (provided by applicant): Systemic Lupus Erythematosus (SLE) is a devastating autoimmune disease that affects up to 0.5% of the US population. This disease is characterized by heterogeneous manifestations including severe rashes, organ- threatening nephritis, and an elevated risk of cardiovascular disease. Despite ongoing research into the pathogenesis of this disease, very little is understood about the mechanism of cutaneous lesion development or how skin inflammation may be able to influence systemic disease. This project proposes to take a systems biology approach to analyze the gene expression changes present in the most common cutaneous lupus subtypes by taking advantage of advances in RNA isolation from formalin-fixed paraffin-embedded tissue. Importantly, changes in gene expression and regulation of inflammatory networks will then be analyzed to determine pathways unique to cutaneous lupus associated with systemic disease. Further, comparisons with known dysregulated pathways in lupus nephritis biopsies will be made to develop an understanding of the overlap in the pathology between cutaneous and renal lupus. Importantly, cutaneous transcriptional changes will be analyzed in the context of available clinical data to determine if cutaneous biomarkers may exist that predict development of systemic lupus. Study Design: Using microarray analysis of subacute cutaneous (sCLE) and discoid lupus (DLE) skin biopsies, AIM 1 will develop a comprehensive understanding of the gene expression changes in sCLE and DLE compared with control skin. Using Ingenuity and Genomatix software, changes to biological pathways and transcriptional networks will be identified. Further, overlapping and unique transcriptional changes between the disease subsets will also be determined. The information gathered in AIM1 and additional biopsy subsets will then be used to compare cutaneous changes in gene expression in skin only CLE to CLE associated with systemic disease (Aim2a). Further, the pathways and networks unique to DLE, sCLE, skin- only CLE and CLE with systemic disease will be compared to those known to be dysregulated in kidney biopsies from lupus nephritis patients via TALE (Tool for Approximate LargE graph matching) analysis (AIM2b). This will allow for identification of overlapping expression changes and inflammatory networks between cutaneous and renal inflammation which may be important targets for further study and treatments. AIM2c will use Chi-squared and survival analysis to determine the extent to which gene expression changes and dysregulated networks identified in AIM 1 correlate with the development of systemic disease manifestations, either at the time of biopsy or over time. This would then allow for development of possible biomarkers of systemic disease risk and identify important targets for disease prevention and treatment strategies.

 描述（由申请人提供）：系统性红斑狼疮（SLE）是一种破坏性自身免疫性疾病，影响高达0.5%的美国人口。这种疾病的特点是异质性的表现，包括严重的皮疹，危及器官的肾炎，和心血管疾病的风险增加。尽管对这种疾病的发病机制正在进行研究，但对皮肤病变发展的机制或皮肤炎症如何影响全身性疾病的机制知之甚少。该项目提出采用系统生物学方法，通过利用福尔马林固定石蜡包埋组织中RNA分离的进展来分析最常见的皮肤狼疮亚型中存在的基因表达变化。重要的是，然后将分析基因表达和炎症网络调节的变化，以确定与全身性疾病相关的皮肤狼疮特有的途径。此外，与已知的狼疮肾炎活检失调途径的比较，将发展皮肤和肾脏狼疮之间的病理重叠的理解。重要的是，将在现有临床数据的背景下分析皮肤转录变化，以确定是否存在预测系统性狼疮发展的皮肤生物标志物。研究设计：使用亚急性皮肤（sCLE）和盘状狼疮（DLE）皮肤活检的微阵列分析，AIM 1将开发一个全面的了解sCLE和DLE与对照皮肤相比的基因表达变化。使用Incidity和Genomatix软件，将确定生物途径和转录网络的变化。此外，还将确定疾病子集之间的重叠和独特的转录变化。然后将在AIM 1和其他活检子集中收集的信息用于比较仅皮肤CLE与全身性疾病相关的CLE（Aim2a）中基因表达的皮肤变化。此外，DLE、sCLE、仅皮肤CLE和具有全身性疾病的CLE特有的途径和网络将通过TALE（近似大E图匹配工具）分析（AIM 2b）与已知在来自狼疮肾炎患者的肾活检中失调的那些进行比较。这将允许识别皮肤和肾脏炎症之间的重叠表达变化和炎症网络，这可能是进一步研究和治疗的重要靶点。AIM2c将使用卡方和生存分析来确定在AIM 1中鉴定的基因表达变化和失调网络与全身性疾病表现的发展相关的程度，无论是在活检时还是随着时间的推移。这将允许开发系统性疾病风险的可能生物标志物，并确定疾病预防和治疗策略的重要目标。