Mass spectrometry-driven systems biologic analysis of salivary MALT lymphoma

描述(申请人提供)：Sj“gren‘s综合征是北美和欧洲第二常见的自身免疫性疾病。大多数唾液腺恶性淋巴瘤被归类为粘膜相关淋巴组织(MALT)型的低度恶性B细胞淋巴瘤，并发生在被称为淋巴上皮性涎腺炎(Lesa)的良性病变的背景下，这种良性病变普遍存在于所有Sj”gren’s综合征患者中。事实上，Lesa是Sj“gren综合征的组织病理学表现。参与Lesa向唾液MALT转变的非调控分子途径尚不清楚。因此，在这一应用中，我们建议利用基于质谱学的蛋白质组学策略，并通过复杂的生物信息学驱动的途径分析来揭示Lesa/Sj”gren综合征唾液MALT发展的潜在分子途径。在具体目标1中，我们将以一种公正的方式进行全球定量蛋白质组分析，并比较LESA淋巴瘤和唾液MALT淋巴瘤的特征，以确定从LESA淋巴瘤向唾液MALT淋巴瘤转变过程中最显著的蛋白质组变化。在特定目标2中，我们将根据在特定目标1中进行的MS/MS实验获得的定量蛋白质组学数据，构建在Lesa到唾液MALT淋巴瘤中发生的非调控通路网络。在特定目标3中，我们将通过研究特定非调控蛋白的异位表达对细胞的影响，从功能上询问参与唾液MALT发生的非调控信号网络中的中心蛋白。在具体目标4中，我们将使用我们为存档和分发MS数据以供进一步审问而开发的工具，将定量MS/MS获得的数据传播给所有用户。我们的研究采用大规模鉴定伴随着LesA向唾液MALT转变的蛋白表达的数量变化，将阐明与发病相关的非调控通路，并识别可能有助于唾液MALT淋巴瘤诊断的易感因素，并可能成为唾液MALT治疗的靶点。我们的研究对于以定量质谱学为基础的方法研究所有形式的癌症的发展具有广泛的意义。项目简介：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Sj“gren综合征发展为唾液腺MALT淋巴瘤过程中与病理相关的途径。重要的是，我们的研究将揭示蛋白质生物标志物，通过它们可以可靠地诊断这种疾病，并将其与涎腺良性淋巴组织增生和其他低级别B细胞淋巴瘤区分开来。识别这些被解除调节的途径也将为针对唾液MALT淋巴瘤发生的潜在病理异常的新疗法的开发提供机会。

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.