NIAMS: CORT

尼亚姆斯：科特

• 批准号: 8924900
• 负责人: ROBERT A. LAFYATIS
• 金额: $ 162.3万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8924900
• 关键词: Affinity; Antibodies; Biological Markers; Cicatrix; Clinical; Clinical Markers; Complex; Coupled; Data; Disease; Disease Marker; Disease Progression; Endothelial Cells; Enrollment; Fatal Outcome; Fibrosis; Genes; HLA-B35 Antigen; Heterogeneity; Interstitial Lung Diseases; Investigation; Minority; Modeling; Molecular; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome Measure; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Population; Populations at Risk; Process; Proteins; Rheumatism; Scientist; Serum; Skin; Stress; Systemic Scleroderma; Testing; Therapeutic Trials; Translational Research; Vascular Diseases; adiponectin; biological adaptation to stress; body system; design; effective therapy; empowered; novel; novel therapeutics; open label; patient oriented research; pulmonary arterial hypertension; research clinical testing; response; skin disorder; targeted treatment; translational study; vascular inflammation

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) is a rare, complex rheumatic disease involving multiple organ systems with a frequently fatal outcome. It remains perhaps the most difficult rheumatic disease to manage, with limited effective therapies. One of the greatest impediments to finding new treatments is the heterogeneity of patient presentation and disease progression. Clinical markers are unable to predict onset and/or progression of the major complications, such as progressive fibrotic skin disease, pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), each seen in a minority of SSc patients. Identification of biomarkers permitting early recognition of these complications would potentially permit more targeted therapies, but also provide enriched "at risk" populations for enrolling in therapeutic trials. We focus in this Center of Research Translation on identifying biomarkers of SSc complications and progression. Empowered by a very large SSc clinical population, we propose careful clinical evaluations (Clinical-Core B), coupled with powerful molecular approaches (Microarray-Core C) to identify skin, serum and peripheral blood mononuclear cell (PBMC) disease biomarkers. We supplement this with strong translational studies into pathogenesis, probing in highly interactive projects fibrosis, vascular inflammation and the stress response in SSc. In Project 1, Dr. Lafyatis, Center Director, will investigate biomarkers in the skin predicting progressive skin disease. This project will also validate a recently identified 4-gene biomarker and test this biomarker as an outcome measure for a novel, short-duration, open-label trial of a high affinity, pan-anti-TGFp antibody. In project 2, Dr. Farber will identify biomarkers predicting the onset of PAH. In overlap with Project 1, these will be compared to biomarkers of ILD and further explored in a new model of PAH, the adiponectin-/- mouse. In Project 3 Dr. Trojanowska will extend data showing expression of HLA-B35, associated with SSc-PAH, induces a stress/unfolded protein response (UPR), and that stress response genes, ATF4 and ATF6 are more broadly upregulated in SSc. She will define the stress/UPR response in PBMCs and endothelial cells, and in overlap with Projects 1 and 2 investigate how the stress response relates to SSc disease activity. RELEVANCE: Systemic sclerosis is a poorly understood and relatively rare, but frequently fatal illness, involving widespread scarring and vascular disease. This project is designed to coordinate multiple scientists and clinicians to accelerate understanding of the disease process through highly interactive patient-oriented studies into markers of disease activity, investigation of pathogenesis and trial of a novel therapeutic.

描述（由申请人提供）：系统性硬化症（SSC）是一种罕见的，复杂的风湿病，涉及多个器官系统，经常发生致命的结果。通过有效的疗法，它可能仍然是最困难的风湿性疾病。寻找新疗法的最大障碍之一是患者表现和疾病进展的异质性。临床标志物无法预测主要并发症的发作和/或进展，例如进行性纤维化皮肤病，肺动脉高压（PAH）和间质性肺病（ILD），每种疾病（ILD）都在少数SSC患者中可见。识别允许早期识别这些并发症的生物标志物可能会允许更多的有针对性的疗法，但也提供了富集的“风险”人群来参加治疗试验。我们将重点放在研究中心转化中，以识别SSC并发症和进展的生物标志物。在非常大的SSC临床人群中，我们提出了仔细的临床评估（临床核B），再加上强大的分子方法（微阵列核C），以鉴定皮肤，血清和外周血单核细胞（PBMC）生物标志物。我们通过对发病机理的大量翻译研究来补充这一点，在高度互动的项目纤维化，血管炎症和SSC中的应力反应中进行了探测。 在项目1中，中心主任Lafyatis博士将调查皮肤中预测性皮肤疾病的生物标志物。该项目还将验证最近确定的4基因生物标志物，并测试该生物标志物，作为对高亲和力，Pan-Anti-TGFP抗体的新型，短期，开放标签试验的结果度量。在项目2中，Farber博士将确定预测PAH发作的生物标志物。在与项目1的重叠中，将它们与ILD的生物标志物进行比较，并在新的PAH模型（脂联素 - / - 小鼠）中进一步探索。在项目3中，Trojanowska博士将扩展数据，显示与SSC-PAH相关的HLA-B35的表达，诱导应力/展开的蛋白质反应（UPR），并且在SSC中，应力响应基因，ATF4和ATF6在SSC中更广泛地上调。她将定义PBMC和内皮细胞中的应力/UPR反应，并与项目1和2重叠，研究应力反应与SSC疾病活性的关系。 相关性：全身性硬化症是一种鲜为人知的，相对较少但经常致命的疾病，涉及广泛的疤痕和血管疾病。该项目旨在协调多个科学家和临床医生，以通过高度互动的以患者为导向的研究来加速对疾病过程的了解，以疾病活动的标志，对新型治疗性的发病机理的研究和试验。