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Caveolae Mediated Bacterial Uptake in the Urinary Tract

小凹介导的尿道细菌摄取

基本信息

批准号：
7809620
负责人：
Soman N Abraham
金额：
$ 36.78万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2011-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Uropathogenic E.coli (UPEC) account for over 80% of urinary tract infections (UTIs). It is now known invasion of the bladder epithelial cells (BECs) is a critical initiating step in UTIs. We have demonstrated that UPEC invasion is localized to distinct cellular entities in the BEG membrane loosely- termed caveolae. These caveolae are comprised of lateral assemblies of cholesterol, lipids and select proteins such as caveolin-1. We hypothesized that the entry of UPEC into BECs is a highly dynamic event and therefore the host-cell proteins that mediate bacterial entry could be proteins that are selectively recruited to caveolae or become activated within these microdomains following exposure to UPEC. Our initial studies have revealed that two proteins, flotillin-1 and annexin-ll, were recruited to caveolae whereas the third, caveolin-1, became tyrosine-phosphorylated following exposure to UPEC. Another finding emerging from proteome analysis of BECs is that a significant proportion of the proteins identified as caveolar components are known to be regulated by cAMP, a major second messenger implicated in regulating luminal surface area of the bladder by triggering endo- and exocytosis of BEG vesicles which serve as repositories of luminal membranes. This finding, revealed possible parallels between caveolae mediated bacterial entry nto BECs and regular endocytosis of luminal membrane by BECs following voiding of urine. The goal of this research proposal is to extend and expand this line of investigation. Therefore, we propose to: ) Elucidate the mechanism by which flotillin-1, annexin-ll, and caveolin-1 contribute to bacterial entry into 3ECs. (2) Use proteome mining approaches to extend the identification of caveolar components essential for UPEC invasion of BECs.(3) Investigate the regulatory role of cAMP on UPEC invasion of BECs and the mpact of modulators of intracellular cAMP in conferring protection against experimental UTIs. We believe that a systematic approach to the identification of caveolar determinants of bacterial entry will provide a comprehensive picture of the dynamic molecular interactions occurring in the invasion process and also yield candidate proteins that could potentially serve as targets for drug therapy.

描述（由申请方提供）：尿路感染（UTI）中80%以上是由尿路致病性大肠杆菌（UPEC）引起的。目前已知膀胱上皮细胞（BEC）的侵袭是UTI的关键起始步骤。我们已经证明UPEC的侵袭定位于BEG膜上不同的细胞实体--松散地称为小窝。这些小窝由胆固醇、脂质和选择的蛋白质如小窝蛋白-1的侧向组装体组成。我们假设UPEC进入BEC是一个高度动态的事件，因此介导细菌进入的宿主细胞蛋白可能是选择性招募到小窝或暴露于UPEC后在这些微域内被激活的蛋白质。我们的初步研究表明，两种蛋白质，flotillin-1和annexin-II，被招募到小窝，而第三，小窝蛋白-1，成为酪氨酸磷酸化后暴露于UPEC。从BEC的蛋白质组分析中出现的另一个发现是，已知被鉴定为小窝组分的蛋白质的显著比例受cAMP调节，cAMP是一种主要的第二信使，其通过触发BEG囊泡的内分泌和胞吐作用来调节膀胱的腔表面积，BEG囊泡作为腔膜的储存库。这一发现揭示了小窝介导的细菌进入BEC和排尿后BEC对管腔膜的规则内吞作用之间可能的相似之处。本研究提案的目标是延伸和扩大这一调查路线。因此，我们建议：）阐明flotillin-1，annexin-II和caveolin-1有助于细菌进入3EC的机制。(2)使用蛋白质组挖掘方法来扩展对UPEC入侵BEC所必需的小窝组分的鉴定。(3)研究cAMP对UPEC侵袭BEC的调节作用以及细胞内cAMP调节剂对实验性UTI的保护作用。我们相信，一个系统的方法来识别细菌进入的小窝决定因素将提供一个全面的动态分子相互作用发生在入侵过程中的图片，也产生候选蛋白，可能作为药物治疗的目标。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

New roles for mast cells in modulating allergic reactions and immunity against pathogens.

DOI：
10.1016/j.coi.2009.09.007
发表时间：
2009-12
期刊：
Current opinion in immunology
影响因子：
7
作者：
Hofmann AM;Abraham SN
通讯作者：
Abraham SN

Ubiquitination of Innate Immune Regulator TRAF3 Orchestrates Expulsion of Intracellular Bacteria by Exocyst Complex.

DOI：
10.1016/j.immuni.2016.06.023
发表时间：
2016-07-19
期刊：
Immunity
影响因子：
32.4
作者：
Miao Y;Wu J;Abraham SN
通讯作者：
Abraham SN

Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues.

肥大细胞通过修复通过感染组织的树突状细胞运输来增强自适应免疫。

DOI：
10.1016/j.chom.2009.09.004
发表时间：
2009-10-22
期刊：
Cell host & microbe
影响因子：
30.3
作者：
Shelburne CP;Nakano H;St John AL;Chan C;McLachlan JB;Gunn MD;Staats HF;Abraham SN
通讯作者：
Abraham SN

Plasticity in mast cell responses during bacterial infections.