Project 1 Biomarkers of disease activity and progression in systemic sclerosis

系统性硬化症（SSc）的特征在于异质性疾病表现和在细胞内的变化。 系统性硬化症（SSc）由于其自身的特点， 异质性的临床表现，疾病进展的变异性和量化的困难， 疾病的程度。异质性疾病进展使得现有临床 工具来告诉谁的皮肤和内部器官疾病将进展，谁将稳定或 自发改善。我们最近发现，皮肤中四种基因的表达与 与改良的Rodnan皮肤评分（MRSS），表明疾病进展的标志物，预测 MRSS的未来变化也可以用适当的临床/病理学样品来鉴定。主要 该建议的第一个目标的焦点是鉴定这样的生物标志物。我们提出了两种方法，利用 RNA表达分析和免疫组织化学研究，靶向血管炎症标记物， 损伤这些研究将与项目2中观察肺部疾病标志物的研究和 目的3观察血管炎症和应激。 疾病活动和进展的生物标志物可能会补充或在早期试验中取代临床 结果指标，如MRSS，可能允许短期（开放标签）试验，其中皮肤评分 通常不会发生重大变化。值得注意的是，有效的促纤维化细胞因子，转化 生长因子-β（TGF β）调节我们的4基因皮肤生物标志物中的两个基因（COMP和THS 1）。我们 在目标2中提出，通过以下方式标准化和验证这种皮肤病的4基因生物标志物的性能： 比较邻近和对侧前臂重复活检的重复性，并通过检查 在短时间和长时间内的变化。最后，在第三个目标中，我们提出了一个短期开放标签 高亲和力泛抗TGF β抗体GC 1008的试验。我们将测试这种抗体 快速抑制4基因生物标志物中的TGF β标签mRNA表达，验证生物标志物的效用 并为使用该试剂的更大临床试验提供初步的概念验证数据。 相关性（参见说明）： 系统性硬化症是一种罕见的疤痕性疾病，影响皮肤和内脏器官，经常导致死亡 肺部、肠道或肾脏受累。在这项提案中，我们将确定血液中的标记物，以更好地 确定哪些患者会发展为严重并发症。我们还将进行一项小型临床试验， 测试一种药物，阻断纤维化（疤痕）体内最有效的调节剂。

Systemic Sclerosis (SSc) is characterized by heterogeneous disease manifestations and variations in disease prSystemic sclerosis (SSc) presents special problems for developing therapies due to the heterogeneous clinical presentation, the variability of disease progression and the difficulty quantifying the extent of disease. Heterogeneous disease progression makes it impossible with currently available clinical tools to tell whose skin and internal organ disease is going to progress, and whose is going to stabilize or improve spontaneously. We have recently shown that expression of four genes in the skin correlates highly with the modified Rodnan skin score (MRSS), suggesting that markers for disease progression, predicting future changes in the MRSS, might also be identified with the proper clinical/pathological samples. The major focus of the first aim in this proposal is to identify such biomarkers. We propose two approaches utilizing RNA expression analyses and immunohistochemical studies targeting markers of vascular inflammation and injury. These studies will overlap with studies in Project 2 looking at markers of lung disease and studies in aim 3 looking at vascular inflammation and stress. Biomarkers of disease activity and progression might supplement or, in early phase trials, replace clinical outcome measures, such as the MRSS, potentially permitting short (open label) trials where the skin score would not normally be expected to change significantly. Notably, the potent profibrotic cytokine, transforming growth factor-p (TGF(3) regulates two of the genes in our 4-gene skin biomarker (COMP and THS1). We propose in aim 2 to standardize and validate the performance of this 4-gene biomarker of skin disease, by comparing reproducibility in biopsies repeated in adjacent and contralateral forearm, and by examining the change over short and longer periods of time. Finally, in the third aim we propose a short-term open label trial of the high affinity pan-anti-TGFp antibody, GC1008. We will test the hypothesize that this antibody will rapidly inhibit TGF(3 signature mRNA expression in the 4-gene biomarker, validating utility of the biomarker and providing preliminary proof-of-concept data for a larger clinical trial using this agent. RELEVANCE (See instructions): Systemic sclerosis is a rare scarring disease affecting skin and internal organs frequently leading to death from lung, intestinal or kidney involvement. In this proposal we will identify markers in the blood to better define which patients will progress to have severe complicaitons. We will also carry out a small clinical trial, testing a medication that blocks the most potent regulator in the body of fibrosis (scarring).