Systems Approach to Sjogren's Syndrome Pathogenesis (SASSP)

描述(申请人提供)：SJ“格伦综合征(SS)是一种进行性器官特异性自身免疫性疾病，影响约400万美国人。这种疾病导致不可逆转的唾液和泪腺组织损伤以及唾液和泪液分泌的丧失，导致这些患者的生活质量显著下降。目前对这一复杂疾病的了解很少，导致没有有效的早期发现技术和有效的治疗方法。更重要的是，大约5%的SS患者进展为恶性淋巴瘤，这是一种致命的后遗症。这项应用旨在从诊断、治疗和预后方面影响对SS发病机制的基本生物学理解和这种自身免疫性疾病的临床结果。RFA DE-08-001促使计算和生物科学领域的多学科科学家团队走到了一起，他们兴奋地致力于实现这些目标。该联盟旨在验证涎腺原发SS(PSS)和淋巴瘤(PSS/MALT)的发病机制与关键细胞内网络、通路和分子靶点的异常活动有关的假说。一个系统的方法已经到位，以确定关键的生物途径和关键的分子决定因素，其价值将得到实验测试和验证。这一迭代过程将最终导致关键分子靶点(关键驱动因素)的出现，这些靶点可以转化为临床诊断、治疗和预后使用。实现这些基本目标和转换目标有三个具体目标。特定目标1是一个实验组件，用于生成具有PSS和淋巴瘤表型的新的、高质量的基础数据库(蛋白质组学和转录组学)。特定目标2是一个计算/模型构建组件，用于将转录和蛋白质组数据库与新开发的现有知识数据库(Sj“gren‘s综合征知识库，SSKB)相集成，并执行网络的荟萃分析，并使用加权基因共表达网络分析(WGCNA)识别PSS发病机制和恶性淋巴瘤转化的关键分子靶点(关键驱动因素)。特定目标3是验证已识别的分子靶标在生物网络中的作用的实验特定目标。在计算机验证中，将使用体内啮齿动物模型和体外细胞系方法来实现疾病模型的全面迭代和验证。SS疾病模型和支持数据库将公开提供。该项目的一个相关成果是对唾液腺发病机制的系统方法的原理证明，即识别关键分子靶点、途径和网络的能力。这些资源(数据库)和计算/建模方法将适用于其他唾液腺疾病和生物学。项目简介：一项新颖而令人兴奋的研究发现了导致干燥综合征和恶性淋巴瘤的关键分子靶点。这些关键分子靶点将使这种主要自身免疫性疾病的诊断、治疗和预后得到更好的发展。

DESCRIPTION (provided by applicant): Sj"gren's Syndrome (SS) is a progressive organ-specific autoimmune disease affecting about 4 million Americans. The disease results in irreversible salivary and lacrimal gland tissue damage and loss of saliva and tear production, leading to significant reduction in the quality of life for these patients. This complex disease is currently poorly understood resulting in no effective early detection technology and the lack of effective therapy. Of further importance is that approximately 5% of SS patients progress to develop malignant lymphoma, a lethal sequelae. This application aims to impact both the fundamental biological understanding of SS pathogenesis and the clinical outcomes of this autoimmune disease, diagnostically, therapeutically and prognostically. The RFA DE-08-001 sparked the coming together of a multi-disciplinary team of scientists in computational and biological sciences excited and committed to achieve these goals. This consortium aims to validate the hypothesis that the pathogenesis of primary SS (pSS) and lymphoma (pSS/MALT) development in salivary glands involve the aberrant activities of key intracellular networks, pathways and molecular targets. A systems approach is in place to identify the key biological pathways and critical molecular determinants whose values will be experimentally tested and validated. This iterative process will lead to the eventual emergence of key molecular targets (key drivers) that can be translated for clinical utilizations for diagnostics, therapeutics and prognostics. Three specific aims are in place to achieve these basic and translational goals. Specific Aim 1 is an experimental component to generate new, high quality foundation databases (proteomics and transcriptomics) of human salivary glands with pSS and lymphoma phenotypes. Specific Aim 2 is a computational/model building component to integrate the transcriptomic and proteomic databases with a newly developed database of existing knowledge (Sj"gren's Syndrome Knowledge Base, SSKB) and perform meta-analysis of networks, and identification of key molecular targets (key drivers) using the weigh-gene co-expression network analysis (WGCNA) for both pSS pathogenesis and malignant lymphoma conversion. Specific Aim 3 is the experimental specific aim to validate the role of the identified molecular targets in the biological network. In silico validations, in vivo rodent models and in vitro cell line approaches will be used to achieve a comprehensive iteration and validation of the disease model. The SS disease model and supporting databases will be made publicly available. A related outcome of this project is the proof of principle of a systems approach to salivary gland pathogenesis, the ability to identify critical molecular targets, pathways and networks. The resources (databases) and computational/modeling approaches will be applicable to other salivary gland diseases and biology. Project Narrative: A novel and exciting research to discover key molecular targets responsible for Sj"gren's syndrome development as well as malignant lymphoma. These key molecular targets will allow development of better diagnostics, therapeutics and prognostics for this major autoimmune disease.