NIAMS: CORT

尼亚姆斯：科特

• 批准号: 8531154
• 负责人: ROBERT A. LAFYATIS
• 金额: $ 154.19万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531154
• 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; Therapy Clinical 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; 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）是一种罕见的复杂风湿性疾病，涉及多个器官系统，经常导致死亡。它可能仍然是最难管理的风湿性疾病，有效的治疗方法有限。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，如进行性纤维化皮肤病、肺动脉高压（PAH）和间质性肺病（ILD），每种并发症均见于少数SSc患者。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有针对性的治疗，但也为参加治疗试验提供了丰富的“高危”人群。我们专注于这个研究翻译中心，以确定SSc并发症和进展的生物标志物。在非常大的SSc临床人群的支持下，我们提出了仔细的临床评估（临床核心B），结合强大的分子方法（微阵列核心C）来鉴定皮肤，血清和外周血单核细胞（PBMC）疾病生物标志物。我们补充这一强大的转化研究的发病机制，在高度互动的项目纤维化，血管炎症和应激反应在SSc探测。 在项目1中，中心主任Lafyatis博士将研究皮肤中预测进行性皮肤病的生物标志物。该项目还将验证最近鉴定的4基因生物标志物，并将该生物标志物作为高亲和力泛抗TGF β抗体的新型、短持续时间、开放标签试验的结果指标进行测试。在项目2中，Farber博士将确定预测PAH发作的生物标志物。与项目1重叠，这些将与ILD的生物标志物进行比较，并在PAH的新模型脂联素-/-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的表达诱导应激/未折叠蛋白反应（UPR），并且应激反应基因ATF 4和ATF 6在SSc中更广泛地上调。她将定义PBMC和内皮细胞中的应激/UPR反应，并与项目1和2重叠，研究应激反应如何与SSc疾病活动相关。 相关性：系统性硬化症是一种知之甚少，相对罕见，但往往致命的疾病，涉及广泛的疤痕和血管疾病。该项目旨在协调多位科学家和临床医生，通过高度互动的以患者为导向的疾病活动标志物研究，发病机制调查和新型治疗方法的试验，加速对疾病过程的理解。