NIAMS: CORT

尼亚姆斯：科特

• 批准号: 8089903
• 负责人: ROBERT A. LAFYATIS
• 金额: $ 165.26万
• 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/8089903
• 关键词: NIAMS; CORT

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、复杂的风湿性疾病，涉及多个器官系统，常常导致致命的后果。它可能仍然是最难治疗的风湿病，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生和/或进展，例如进行性纤维化皮肤病、肺动脉高压 (PAH) 和间质性肺疾病 (ILD)，这些并发症均见于少数 SSc 患者。识别生物标志物可以早期识别这些并发症，这可能会允许更有针对性的治疗，但也可以提供丰富的“高危”人群来参加治疗试验。我们的研究转化中心致力于识别 SSc 并发症和进展的生物标志物。凭借庞大的 SSc 临床人群，我们建议进行仔细的临床评估 (Clinical-Core B)，并结合强大的分子方法 (Microarray-Core C) 来识别皮肤、血清和外周血单核细胞 (PBMC) 疾病生物标志物。我们通过对发病机制的强有力的转化研究来补充这一点，探索高度互动的项目纤维化、血管炎症和 SSc 的应激反应。 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确定的 4 基因生物标志物，并测试该生物标志物作为高亲和力、泛抗 TGFp 抗体的新型、短期、开放标签试验的结果衡量标准。在项目 2 中，Farber 博士将确定预测 PAH 发病的生物标志物。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 表达会诱导应激/未折叠蛋白反应 (UPR)，并且应激反应基因 ATF4 和 ATF6 在 SSc 中更广泛上调。她将定义 PBMC 和内皮细胞中的应激/UPR 反应，并与项目 1 和 2 重叠地研究应激反应与 SSc 疾病活动的关系。 相关性：系统性硬化症是一种人们知之甚少且相对罕见的疾病，但往往是致命的疾病，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、发病机制调查和新疗法试验，加速对疾病过程的了解。