Mass spectrometry-driven systems biologic analysis of salivary MALT lymphoma

描述（由申请人提供）：格林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）型的低级别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发生，LESA普遍存在于所有Sj"gren's综合征患者中。实际上，LESA是Sj"gren's综合征的组织病理学表现。从LESA到唾液MALT的转变过程中涉及的解除管制的分子途径尚不清楚。因此，在本应用中，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's综合征唾液MALT发展背后的潜在分子途径失调。在Specific Aim 1中，我们将以公正的方式进行全球定量蛋白质组学分析，并比较LESA和唾液MALT淋巴瘤的特征，以确定从LESA到唾液MALT淋巴瘤转变过程中最重要的蛋白质组学变化。在Specific Aim 2中，我们将基于在Specific Aim 1中进行的MS/MS实验中获得的定量蛋白质组学数据，构建发生在LESA到唾液MALT淋巴瘤的失调通路网络。在Specific Aim 3中，我们将通过研究所选的失调蛋白的异位表达对细胞的影响，从功能上询问参与唾液MALT发育的失调信号网络中的中心蛋白。在具体目标4中，我们将通过使用我们开发的工具将定量质谱/质谱获得的数据传播给所有用户，以存档和分发质谱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转变的蛋白表达的定量变化，将阐明与发病相关的解除调控途径，并确定解除调控途径中的易感因子，这可能有助于唾液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研究所有形式癌症的发展具有广泛的意义。项目描述：涎腺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Sj"gren's综合征发展为唾液MALT淋巴瘤过程中失调的病理相关通路。重要的是，我们的研究将揭示这种疾病可能可靠诊断的蛋白质生物标志物，并将其与涎腺的良性淋巴样增生和其他低级别b细胞淋巴瘤区分开来。对失调通路的识别也将为开发针对唾液MALT淋巴瘤潜在发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.