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Par1-substrates responsible for CagA-mediated pathogenesis of Helicobacter pylori

Par1-底物负责 CagA 介导的幽门螺杆菌发病机制

基本信息

批准号：
8508205
负责人：
ANNE MUESCH
金额：
$ 49.15万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-10 至 2017-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Par1-substrates responsible for CagA-mediated pathogenesis of Helicobacter pylori Gastritis and gastric carcinoma, the second leading cause of cancer-related deaths in the world, have been linked to infection with Helicobacter pylori, a bacterium that colonizes the gastric mucosa. H. pylori strains that harbor a gene called cytotoxin-associated gene A (CagA) are more virulent and present a much higher cancer risk for their host than strains that lack CagA and recently the toxin has been shown to function as an oncoene in mice. CagA induces loss of cell polarity, increased cell migration and apoptosis of gastric epithelial cells and promotes aberrant growth signals by activating the Ras-MAP-cascade. Recently, we and others have identified the serine/threonine kinase Par1 as a CagA-target responsible for epithelial polarity defects associated with H. pylori pathology. The challenge at hand now is to delineate the CagA signaling pathway(s) downstream of Par1. Although a known polarity determinant, Par1-substrates that mediate mammalian epithelial polarity have not yet been discerned. In preliminary experiments, we have developed an unbiased Par1 substrate screen that enabled us to identify 63 putative substrates, most of them novel, and their precise Par1b phosphorylation sites in epithelial cells. Our goal is to evaluate the contribution of all validated substrates to CagA-mediated loss of epithelial cell shape and polarity. Since we have determined that Par1b inhibits proliferation and negatively regulates mTOR signaling in epithelial cells, we will also evaluate whether Par1b substrates are relevant for the effects of CagA on proliferation. In a two-tiered approach we will first characterize Par1b substrates downstream of CagA in the kidney-derived epithelial model cell line MDCK and subsequently validate their significance for H. pylori infection of primary human gastric epithelia

描述（由申请方提供）：负责CagA介导的幽门螺杆菌Gap和胃癌发病机制的Par 1-底物（世界上癌症相关死亡的第二大原因）与幽门螺杆菌（一种定植于胃粘膜的细菌）感染有关。H.携带细胞毒素相关基因A（CagA）的幽门螺杆菌菌株比缺乏CagA的菌株毒性更强，对宿主的癌症风险更高，最近该毒素已被证明在小鼠中起致癌作用。CagA通过激活Ras-MAP级联反应诱导胃上皮细胞极性丧失、细胞迁移和凋亡增加，并促进异常生长信号。最近，我们和其他人已经确定了丝氨酸/苏氨酸激酶Par 1作为CagA靶点，负责与H相关的上皮极性缺陷。幽门病理学目前的挑战是描绘Par 1下游的CagA信号通路。虽然一个已知的极性决定因素，Par 1-底物介导的哺乳动物上皮极性尚未被识别。在初步实验中，我们开发了一种无偏见的Par 1底物筛选，使我们能够识别63种推定的底物，其中大多数是新型的，以及它们在上皮细胞中精确的Par 1b磷酸化位点。我们的目标是评估所有经验证的底物对CagA介导的上皮细胞形状和极性丧失的贡献。由于我们已经确定Par 1b抑制上皮细胞的增殖并负调节mTOR信号传导，我们还将评估Par 1b底物是否与CagA对增殖的影响相关。在一个两层的方法中，我们将首先描述Par 1b 底物下游的CagA在肾衍生的上皮模型细胞系MDCK，并随后验证其意义H。幽门螺杆菌对人胃上皮细胞的感染