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（由适用提供）：全身性红斑狼疮（SLE）是一种毁灭性的自身免疫性疾病，影响美国人群的0.5％。该疾病的特征是异质表现，包括严重皮疹，威胁肾炎和心血管疾病风险升高。尽管对这种疾病的发病机理进行了持续的研究，但对皮肤病变发育的机制或皮肤炎症的机理几乎没有理解。该项目的建议是采用系统生物学方法来分析最常见的皮肤狼疮亚型中存在的基因表达变化，它利用了从福尔马林固定的石蜡包含的组织中的RNA分离的进步。重要的是，将分析基因表达和调节的变化，以确定与全身性疾病相关的皮肤狼疮的途径。此外，将进行与狼疮肾炎活检中已知失调途径的比较，以发展对皮肤和肾狼疮之间病理学的重叠的理解。重要的是，将在可用的临床数据的背景下分析皮肤转录变化，以确定是否可能存在预测全身性狼疮发展的皮肤生物标志物。研究设计：使用微阵列分析亚急性皮肤（SCLE）和盘状狼疮（DLE）皮肤活检，AIM 1将对与对照皮肤相比SCLE和DLE中的基因表达变化有了全面的了解。使用Ingenity和Genomatix软件，将确定生物学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AIM1中收集的信息和其他活检子集将用于比较皮肤中仅CLE与全身性疾病相关的皮肤中的皮肤变化（AIM2A）。此外，将将DLE，SCLE，皮肤 - 仅具有全身性疾病的CLE和CLE的途径和网络与通过狼疮肾炎患者的肾脏活检中已知失调的途径和网络进行比较，该故事（用于大约大图匹配的工具）分析（AIM2B）。这将允许鉴定皮肤和肾脏感染之间重叠的表达变化和炎症网络，这可能是进一步研究和治疗的重要目标。 AIM2C将使用卡方和生存分析来确定AIM 1中基因表达发生变化的程度，而在AIM 1中鉴定出的网络与全身性疾病表现的发展（随着时间的流逝或随着时间的流逝）相关。然后，这将允许开发系统性疾病风险的可能生物标志物，并确定预防疾病和治疗策略的重要目标。