Molecular Markers in Discoid Lupus Erythematous

盘状红斑狼疮的分子标记

• 批准号: 8688909
• 负责人: Benjamin Franklin Chong
• 金额: $ 12.3万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688909
• 关键词: Affect; Apoptosis; Award; Biopsy; Blood Circulation; CD8B1 gene; CXCL10 gene; CXCR3 gene; Carbon; Cell Culture Techniques; Cell Surface Proteins; Cell surface; Cells; Cellular Immunity; Cicatrix; Classification; Clinical Investigator; Clinical Sciences; Complement Factor B; Culture Media; Cutaneous; Cutaneous Lupus Erythematosus; Data; Development Plans; Diagnosis; Diagnostic Procedure; Discoid Lupus Erythematosus; Disease; Disease Progression; Education; Etiology; Flow Cytometry; Foundations; Funding; Gender; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Goals; Granzyme; Human; Immunologics; Immunology; Individual; Inflammatory; Inflammatory Infiltrate; Interferon Type I; Interferons; Knowledge; Lesion; Link; Lupus; Medical center; Mentors; Mentorship; Molecular Profiling; Mus; Nuclear; PI3K/AKT; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Physicians; Play; Polymerase Chain Reaction; Proteins; Research Project Grants; Research Proposals; Resources; Role; Site; Skin; Skin Aging; Symptoms; Systemic Lupus Erythematosus; Systemic disease; T-Lymphocyte; Tantalum; Texas; Time; Training; Translational Research; Tumor Necrosis Factor Receptor; United States National Institutes of Health; Universities; Ursidae Family; base; career; career development; cytokine; cytotoxic; disability; disease registry; human FRAP1 protein; insight; lupus-like; molecular marker; new therapeutic target; novel strategies; protein expression; skin lesion; treatment planning

DESCRIPTION (provided by applicant): The NIH K23 mentored award provides the necessary foundation for me to fulfill my career goals of being an independently-funded clinical investigator focusing on the gene and immunologic profiles of cutaneous lupus erythematosus (CLE) patients and becoming an expert in forecasting systemic involvement in CLE patients. The mentored award will also help me achieve my immediate goals of obtaining expertise in microarrays and skin immunology, and establishing a disease registry. Under the auspices of the University of Texas Southwestern (UTSW) Medical Center, I hope to attain these objectives through: 1) mentorship from a group of nationally recognized physicians who are experts in microarrays and skin immunology, and have established disease registries, and 2) classroom education and research resources afforded through the NIH Clinical and Translational Science Award at UTSW. My mentored research project centers on discoid lupus erythematosus (DLE), a disease whose etiology is not well understood. Because of its association with systemic lupus erythematosus (SLE), discoid skin lesions represent an untapped, yet easily accessible resource that could bear great relevance to SLE pathogenesis. This project seeks to identify genes distinctive to DLE (Aim 1), proteins highly expressed by DLE skin resident T cells (Aim 2), and genes linked to systemic spread in DLE subjects (Aim 3). Aim 1 compares gene expression profiles of the skin of DLE subjects without SLE (DLE-only) and normal controls to better define DLE. We will perform microarray analyses on active discoid lesional skin and age-, gender-, and site-matched normal skin. We predict that DLE- only skin will up-regulate type I interferon-regulated and cell-mediated immunity genes versus normal skin. Aim 2 centers on protein expression of skin resident T cells, which dominate the inflammatory cell infiltrate in discoid lesions. We will isolate these T cells from DLE-only and normal skin biopsies placed on top of tantalum- coated carbon matrices and perform flow cytometry analyses to compare T cell surface protein (Study 2a) and intracellular cytokine and cytotoxic protein expression (Study 2b). We postulate that compared with their normal counterparts, DLE-only skin resident T cells will have higher expression of cell surface, cytokine, and cytotoxic proteins associated with TH1 and CD8+ T cells. Aim 3 will contrast gene profiles in DLE subjects with SLE (DLE+SLE) and DLE-only subjects to identify genes associated with systemic spread in DLE. We will perform microarray analyses on active lesional skin (Study 3a) and peripheral blood mononuclear cells (Study 3b) from both groups. We hypothesize that DLE+SLE subjects will up-regulate expression of genes regulated by tumor necrosis factor receptor, nuclear factor-¿B, and PI3K/AKT/mTOR pathways compared with DLE-only subjects. Identification of genes and proteins up-regulated in DLE skin and DLE skin resident T cells, respectively, will provide greater clarity to disease pathogenesis. Moreover, knowledge of genes associated with systemic involvement in DLE subjects will enhance understanding of disease course.

描述（由申请人提供）：NIH K23指导奖为我实现职业目标提供了必要的基础，我的职业目标是成为一名独立资助的临床研究者，专注于皮肤红斑狼疮（CLE）患者的基因和免疫学特征，并成为预测CLE患者全身受累的专家。指导奖还将帮助我实现我的直接目标，获得微阵列和皮肤免疫学方面的专业知识，并建立疾病登记处。在得克萨斯大学西南医学中心（UTSW）的赞助下，我希望通过以下方式实现这些目标：1）来自一群国家认可的医生的指导，他们是微阵列和皮肤免疫学方面的专家，并建立了疾病登记处，2）通过UTSW的NIH临床和转化科学奖提供的课堂教育和研究资源。我指导的研究项目集中在盘状红斑狼疮（DLE），一种病因尚不清楚的疾病。由于其与系统性红斑狼疮（SLE），盘状皮肤病变代表了一个尚未开发的，但容易获得的资源，可能承担很大的相关性SLE的发病机制。该项目旨在鉴定DLE特有的基因（Aim 1），DLE皮肤驻留T细胞高度表达的蛋白质（Aim 2），以及与DLE受试者全身扩散相关的基因（Aim 3）。目的1比较无SLE的DLE受试者（仅DLE）和正常对照皮肤的基因表达谱，以更好地定义DLE。我们将对活跃的盘状病变皮肤和年龄、性别和部位匹配的正常皮肤进行微阵列分析。我们预测，与正常皮肤相比，仅DLE皮肤将上调I型干扰素调节和细胞介导的免疫基因。目的2：研究盘状病变中皮肤驻留T细胞的蛋白表达，这些T细胞主导炎性细胞浸润。我们将从放置在钽包被的碳基质上的仅DLE和正常皮肤活检组织中分离这些T细胞，并进行流式细胞术分析以比较T细胞表面蛋白（研究2a）和细胞内细胞因子和细胞毒性蛋白表达（研究2b）。我们推测，与正常的对应物相比，DLE仅皮肤驻留T细胞将具有与TH 1和CD 8 + T细胞相关的细胞表面、细胞因子和细胞毒性蛋白的更高表达。目的3将比较DLE受试者与SLE（DLE+SLE）和仅DLE受试者的基因谱，以确定与DLE全身扩散相关的基因。我们将对两组的活动性病变皮肤（研究3a）和外周血单核细胞（研究3b）进行微阵列分析。我们假设DLE+SLE受试者与仅DLE受试者相比，将上调肿瘤坏死因子受体、核因子-B和PI 3 K/AKT/mTOR通路调控的基因表达。分别鉴定DLE皮肤和DLE皮肤驻留T细胞中上调的基因和蛋白质将为疾病发病机制提供更大的清晰度。此外，与DLE受试者全身受累相关的基因的知识将增强对疾病过程的理解。