Project 1 Biomarkers of disease activity and progression in systemic sclerosis

系统性硬化症(SSC)的特点是不同的疾病表现和变异。 系统性硬化症(SSC)是开发治疗方法的特殊问题，原因是 不同的临床表现，疾病进展的多样性和量化的困难 疾病的程度。疾病的异质性发展使得目前可用的临床上不可能 工具，以判断谁的皮肤和内脏疾病会恶化，谁的会稳定或 自发地改进。我们最近发现，皮肤中四种基因的表达高度相关。 用改良的罗德南皮肤评分(MRSS)，提示疾病进展的标志物，预测 未来MRSS的变化，也可以通过适当的临床/病理样本来确定。少校 这项提案的第一个目标是确定这样的生物标志物。我们提出了两种利用 针对血管炎症标记物的RNA表达分析和免疫组织化学研究 受伤。这些研究将与项目2中关于肺部疾病标志物的研究以及 目的3观察血管炎症和应激反应。 疾病活动和进展的生物标志物可能会在早期试验中补充或取代临床 结果指标，如MRSS，潜在地允许皮肤评分的短期(开放标签)试验 通常预计不会发生重大变化。值得注意的是，强大的促纤维化细胞因子，转化 生长因子-β(TGF(3))调节我们的四基因皮肤生物标志物中的两个基因(comp和THS1)。我们 在目标2中建议标准化和验证这种皮肤病的4基因生物标记物的性能，通过 比较邻近前臂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发生变化。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PAN抗TGFp抗体GC1008的实验研究我们将测试这种抗体将会 快速抑制转化生长因子(3)标志物在4基因生物标志物中的表达，验证该生物标志物的实用性 并为使用该制剂的更大规模的临床试验提供初步的概念验证数据。 相关性(请参阅说明)： 系统性硬化症是一种罕见的疤痕疾病，影响皮肤和内脏，经常导致死亡。 由肺、肠道或肾脏受累。在这项提案中，我们将识别血液中的标志物，以更好地 明确哪些患者会进展为出现严重并发症。我们还将进行一项小型临床试验， 测试一种药物，该药物可以阻断体内最有效的纤维化调节因子(疤痕形成)。

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).