Mass spectrometry-driven systems biologic analysis of salivary MALT lymphoma

描述（由申请人提供）：干燥综合征是北美和欧洲第二常见的自身免疫性疾病。大多数涎腺恶性淋巴瘤被归类为粘膜相关淋巴组织（MALT）型低度B细胞淋巴瘤，并在称为淋巴上皮性涎腺炎（LESA）的良性病变的背景下出现，LESA普遍存在于所有Sj“gren综合征患者中。事实上，LESA是干燥综合征的组织病理学表现。参与从LESA到唾液MALT的转变的失调分子途径是未知的。因此，在本申请中，我们建议利用基于质谱的蛋白质组学策略，通过复杂的生物信息学驱动的途径分析来揭示LESA/Sj“gren综合征的唾液MALT发展的潜在分子途径失调。在特定目标1中，我们将以无偏的方式进行全球定量蛋白质组学分析，并比较LESA和唾液MALT淋巴瘤的概况，以确定从LESA到唾液MALT淋巴瘤转变中涉及的最显著的蛋白质组学变化。在特定目标2中，我们将基于特定目标1中进行的MS/MS实验获得的定量蛋白质组学数据，构建LESA至唾液腺MALT淋巴瘤中发生的去调控通路网络。在具体目标3中，我们将通过研究所选失调蛋白异位表达的细胞效应，在功能上询问参与唾液MALT发展的失调信号网络中的中心蛋白。在具体目标4中，我们将使用我们开发的工具将定量MS/MS获得的数据传播给所有用户，以存档和分发MS数据以供进一步询问。我们的研究采用大规模鉴定伴随LESA向唾液MALT过渡的蛋白质表达的定量变化，将阐明病理相关的失调途径，并鉴定失调途径中的易感因素，这些因素可能有助于唾液MALT淋巴瘤的诊断，并可能成为唾液MALT治疗的靶点。我们的研究对基于定量质谱的方法用于调查所有形式癌症发展的潜力具有广泛的影响。项目叙述：唾液MALT淋巴瘤发病机制的生物学改变尚不清楚。我们的研究将确定在干燥综合征发展为唾液腺MALT淋巴瘤过程中失调的致病相关通路。重要的是，我们的研究将揭示蛋白质生物标志物，通过这些生物标志物可以可靠地诊断这种疾病，并与唾液腺的良性淋巴样增生和其他低度B细胞淋巴瘤区分开来。鉴定失调的通路也将为开发针对唾液MALT淋巴瘤中发生的潜在致病异常的新疗法提供机会。

DESCRIPTION (provided by applicant): Sj"gren's syndrome is the second most common form of autoimmune disease in North America and Europe. Most malignant lymphomas of the salivary gland are classified as low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type, and arise in the background of a benign lesion known as lymphoepithelial sialadenitis (LESA) which is universally present in all patients with Sj"gren's syndrome. In effect the LESA is the histopathological manifestation of Sj"gren's syndrome. The deregulated molecular pathways involved in the transition from LESA to salivary MALT are unknown. Accordingly, in this application, we propose to utilize a mass spectrometry-based proteomics strategy potentiated by sophisticated bioinformatics-driven pathway analyses to uncover the underlying molecular pathway deregulation underlying the development of salivary MALT from LESA/Sj"gren's syndrome. In Specific Aim 1, we will perform global quantitative proteomic analysis in an unbiased fashion and compare the profiles of LESA and salivary MALT lymphoma to determine the most significant proteomic changes involved in the transition from LESA to salivary MALT lymphoma. In Specific Aim 2, we will construct the deregulated pathway networks that occur in LESA to salivary MALT lymphoma based on the quantitative proteomic data obtained from MS/MS experiments performed in Specific Aim 1. In Specific Aim 3, we will functionally interrogate the central proteins in the deregulated signaling networks involved in development of salivary MALT by investigating the cellular effects of ectopic expression of selected deregulated proteins. In Specific Aim 4, we will disseminate the data obtained by quantitative MS/MS to all users using tools that we have developed to archive and distribute MS data for further interrogation. Our studies employing large-scale identification of quantitative changes in protein expression that accompany the transition of LESA to salivary MALT will elucidate the pathogenetically-relevant deregulated pathways and identify susceptible elements in the deregulated pathways that may facilitate the diagnosis of salivary MALT lymphoma, and may be targeted for salivary MALT therapy. Our studies have broad implications for the potential of quantitative mass spectrometry-based approaches for the investigation of the development of all forms of cancer. Project Narrative: The biologic alterations underlying the pathogenesis of salivary MALT lymphomas are unknown. Our studies will identify the pathogenetically relevant pathways that are deregulated in the progression of Sj"gren's syndrome to salivary MALT lymphoma. Importantly, our studies will reveal protein biomarkers by which this disease may be reliably diagnosed, and distinguished from benign lymphoid proliferations of the salivary gland and other low-grade B-cell lymphomas. Identification of the deregulated pathways will also provide opportunities for the development of novel therapies that target the underlying pathogenetic abnormalities that occur in salivary MALT lymphoma.