Systems Approach to Sjogren's Syndrome Pathogenesis (SASSP)

描述（由申请人提供）：干燥综合征（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的唾液和泪腺组织损伤以及唾液和泪液产生的损失，导致这些患者的生活质量显著降低。这种复杂的疾病目前知之甚少，导致没有有效的早期检测技术和缺乏有效的治疗方法。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。本申请旨在影响SS发病机制的基本生物学理解和这种自身免疫性疾病的诊断，治疗和诊断的临床结果。RFA DE-08-001激发了计算和生物科学领域的多学科科学家团队的热情，并致力于实现这些目标。该联盟旨在验证以下假设：唾液腺中原发性SS（pSS）和淋巴瘤（pSS/MALT）发展的发病机制涉及关键细胞内网络、途径和分子靶点的异常活动。一个系统的方法是到位，以确定关键的生物途径和关键的分子决定因素，其价值将实验测试和验证。这种迭代过程将导致最终出现关键分子靶标（关键驱动因素），这些靶标可以转化为诊断，治疗和药物的临床应用。为实现这些基本和转化目标，有三个具体目标。Specific Aim 1是一个实验组件，用于生成具有pSS和淋巴瘤表型的人唾液腺的新的高质量基础数据库（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，用于将转录组学和蛋白质组学数据库与新开发的现有知识数据库（干燥综合征知识库，SSKB）整合，并使用权重基因共表达网络分析（WGCNA）对pSS发病机制和恶性淋巴瘤转化进行网络荟萃分析和关键分子靶标（关键驱动因素）鉴定。具体目标3是验证所识别的分子靶标在生物网络中的作用的实验具体目标。计算机模拟验证、体内啮齿动物模型和体外细胞系方法将用于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唾液腺发病机制的系统方法的原理证明，以及识别关键分子靶点、途径和网络的能力。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。项目叙述：一项新的和令人兴奋的研究，以发现关键的分子靶点负责干燥综合征的发展以及恶性淋巴瘤。这些关键的分子靶点将允许为这种主要的自身免疫性疾病开发更好的诊断，治疗和预防方法。

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.