Mucosal Immune Barrier in Infection and Immunity

感染和免疫中的粘膜免疫屏障

• 批准号: 8317710
• 负责人: Keith E Mostov
• 金额: $ 123.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317710
• 关键词: Mucosal; Immune; Barrier; Infection; Immunity

DESCRIPTION (provided by applicant): Overview of Program Project: This is a resubmission of a renewal of a Program Project Grant (PPG) application to study the mucosal barrier in infection and inflammation. Ninety-five percent of infectious agents enter through exposed mucosal surfaces, such as the respiratory, gastrointestinal, mammary and urogenital tracts. Mucosal infections include bacterial and viral pneumonia, SARS, TB, AIDS and other sexually transmitted diseases, numerous opportunistic, emerging and re-emerging infections, and biological warfare/terrorist agents. Mucosal surfaces are lined by epithelial cells, usually in a monolayer. The epithelial cell layer is the principal barrier to entry of infectious agents, allergens and other noxious antigens. Fundamentally, the epithelial layer is the most basic component of the innate mucosal immune system. In this Program Project we focus on two broad and inter-related areas of how the epithelial layer performs its functions in mucosal immune protection, with a particular emphasis on pulmonary epithelium. Projects 1 (Mostov), 2 (Engel) and 3 (Rosen) study mechanisms of epithelial wound healing, the roles of sulfs (sulfatases which modify heparan sulfate proteoglycans) in epithelial response to injury and the interaction of polarized cells with a bacterial pathogen. Project 4 (Werb) is focused on how inflammatory cells cross the epithelial barrier to enter the lumen of the organ. Project 1 uses two novel three dimensional cell culture models of epithelial wound healing. Project 2 focuses on the opportunistic pathogen, Pseudomonas aeruginosa, as a model for epithelial pathogen interaction. Project 3 examines how sulfs participate in epithelial wound healing. Project 4 focuses on the role of proteases and sulfs in regulating inflammatory cell recruitment and migration in mucosal tissues. Core A supports the Program Project administratively. Core B (Matthay) provides primary human and rodent lung epithelial cells in monolayer cultures, three-dimensional models and lung slices, as well as functional studies in mice. Core C has an array of four microscopes suitable for three- and four-dimensional analysis of cell dynamics for in vitro studies as well as experiments in living, anesthetized mice. Most infectious agents enter the body through exposed mucosal surfaces. These surfaces are lined by epithelial cells, most commonly in a single layer. We are studying how this epithelial barrier protects us against infection.

描述(由申请人提供)：计划项目概述：这是重新提交的计划项目拨款(PPG)申请的续期，以研究感染和炎症中的粘膜屏障。95%的感染源通过暴露的粘膜表面进入，如呼吸道、胃肠道、乳房和泌尿生殖道。粘膜感染包括细菌性和病毒性肺炎、SARS、结核病、艾滋病和其他性传播疾病、许多机会性、新出现和重新出现的感染，以及生物战/恐怖分子。粘膜表面由上皮细胞排列，通常是单层的。上皮细胞层是感染性物质、过敏原和其他有害抗原进入的主要屏障。从根本上说，上皮层是天然粘膜免疫系统最基本的组成部分。在这个计划项目中，我们关注上皮层如何在粘膜免疫保护中发挥其功能的两个广泛和相互关联的领域，特别是肺上皮。项目1(Mostov)、项目2(Engel)和项目3(Rosen)研究了上皮伤口愈合的机制，硫磺(修饰硫酸乙酰肝素蛋白多糖的硫酸盐酶)在上皮损伤反应中的作用，以及极化细胞与细菌病原体的相互作用。项目4(WERB)的重点是炎症细胞如何穿过上皮屏障进入器官的管腔。项目1使用了两种新的上皮伤口愈合的三维细胞培养模型。项目2的重点是机会致病菌，铜绿假单胞菌，作为上皮性病原体相互作用的模型。项目3考察了硫磺是如何参与上皮伤口愈合的。项目4的重点是蛋白水解酶和硫化物在调节粘膜组织中炎性细胞的募集和迁移中的作用。核心A对计划项目提供行政支持。Core B(Matthay)提供单层培养的原代人类和啮齿动物肺上皮细胞、三维模型和肺切片，以及小鼠的功能研究。Core C有一个由四个显微镜组成的阵列，适用于细胞动力学的三维和四维分析，用于体外研究以及活体麻醉小鼠的实验。 大多数感染性物质通过暴露的粘膜表面进入人体。这些表面由上皮细胞排列，最常见的是单层。我们正在研究这种上皮屏障是如何保护我们免受感染的。

项目成果

Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis.

• DOI: 10.1038/onc.2009.365
• 发表时间: 2010-02-04
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Lemjabbar-Alaoui, H.;van Zante, A.;Singer, M. S.;Xue, Q.;Wang, Y-Q;Tsay, D.;He, B.;Jablons, D. M.;Rosen, S. D.
• 通讯作者: Rosen, S. D.

The second type VI secretion system of Pseudomonas aeruginosa strain PAO1 is regulated by quorum sensing and Fur and modulates internalization in epithelial cells.

• DOI: 10.1074/jbc.m112.376368
• 发表时间: 2012-08-03
• 期刊: The Journal of biological chemistry
• 作者: Sana TG;Hachani A;Bucior I;Soscia C;Garvis S;Termine E;Engel J;Filloux A;Bleves S
• 通讯作者: Bleves S

Pseudomonas aeruginosa pili and flagella mediate distinct binding and signaling events at the apical and basolateral surface of airway epithelium.

• DOI: 10.1371/journal.ppat.1002616
• 发表时间: 2012
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Bucior I;Pielage JF;Engel JN
• 通讯作者: Engel JN

Endosulfatases SULF1 and SULF2 limit Chlamydia muridarum infection.

• DOI: 10.1111/cmi.12133
• 发表时间: 2013-09
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Kim JH;Chan C;Elwell C;Singer MS;Dierks T;Lemjabbar-Alaoui H;Rosen SD;Engel JN
• 通讯作者: Engel JN

Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae.

• DOI: 10.4049/jimmunol.1003449
• 发表时间: 2011-06-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Hong JS;Greenlee KJ;Pitchumani R;Lee SH;Song LZ;Shan M;Chang SH;Park PW;Dong C;Werb Z;Bidani A;Corry DB;Kheradmand F
• 通讯作者: Kheradmand F