Mpeg1 in Innate Immunity

先天免疫中的 Mpeg1

基本信息

批准号：
8880309
负责人：
ECKHARD R PODACK
金额：
$ 38.38万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880309
关键词：
Abscess Acid Fast Bacillae Staining Method Anti-Bacterial Agents Antibiotic Resistance Bacteremia Bacteria Bacterial Infections Bone Marrow Breeding Cell Lineage Cells Colitis Colon Crohn&apos s disease Cytolysis Data Diarrhea Disease model Endosomes Epithelial Generations Genus Mycobacterium Health Immune system In Vitro Infection Infectious Skin Diseases Inflammation Inflammatory Bowel Diseases Inflammatory Response Integral Membrane Protein Knockout Mice Lymphoid Cell Measures Mediating Membrane Mesenchymal Modeling Molecular Mucosal Immunity Mucous body substance Muramidase Mus Myeloid Cells Natural Immunity P-2 Partner in relationship Pathogenesis Peritoneal Macrophages Phagosomes Pharmaceutical Preparations Predisposition Proteins Role Salmonella Salmonella infections Salmonella typhimurium Skin Sodium Dextran Sulfate Testing Vacuole Vesicle Water Weight Work acid fast bacteria bactericide drinking drug development insight interest keratinocyte killings methicillin resistant Staphylococcus aureus microbiome novel pathogenic bacteria perforin 2 polymerization porin

项目摘要

DESCRIPTION (provided by applicant): In this revised application we show that Perforin-2 (Mpeg1) deficient mice are unable to clear orogastric infection with Salmonella typhimurium and epicutaneous infection with methicillin resistant Staphylococcus aureus (MRSA). Wild type, Perforin-2 sufficient littermates clear both types of bacteria. These findings support our previous in vitro data that showed that Perforin-2 is essential for clearing intracellular bacterial infections. Perforin-2 is expressed ubiquitously: constitutive or inducible by IFNs in all cells derived from endodermal, ectodermal, neuroectodermal and mesenchymal cells. Our data also suggest that killing of bacteria inside cells is responsible fo the inflammatory response observed in bacterial infections and required for bacterial clearance. Our new data in the dextran sodium sulfate model of inflammatory bowel disease suggest that P-2 is responsible for causing the inflammatory response providing novel insights into the pathogenesis of IBD which may be important for developing treatment options for Crohn's disease. In addition, the role of P-2 for anti-bacterial defense provides opportunities for drug development against antibiotic resistant bacterial infections. In ths application we will pursue work in three specific aims. In the first aim we will study mucosal immunity in P-2 sufficient and P-2 deficient mice to orogastric infection with Salmonela typhimurium and determine the role and molecular mechanisms of the inflammatory response in relation to P-2. In the second specific aim we will study the role of P-2 in the induction of diarrhea in the disease model of dextran sodium sulfate (DSS) and the role of P-2 in the composition of the microbiome. In the third specific aim, the susceptibility of P-2 deficint mice to methicillin resistant Staphylococcus aureus (MRSA) will be investigated and the molecular mechanism of P-2 mediated killing of MRSA in keratinocytes studied.

描述（由申请人提供）：在此修订后的应用中，我们表明，缺陷的小鼠无法用鼠伤寒沙门氏菌和耐甲氧西林抗甲氧西林的金黄色葡萄球菌（MRSA）清除胃胃感染。野生型，穿孔2足够的同窝仔清除两种类型的细菌。这些发现支持了我们以前的体外数据，这些数据表明，穿孔蛋白-2对于清除细胞内细菌感染至关重要。 Perforin-2普遍表达：在所有源自内胚层，外胚层，神经皮质和间质细胞的细胞中，由IFN诱导或诱导。我们的数据还表明，细胞内细菌的杀死是导致细菌感染中观察到的炎症反应的原因，细菌清除所需的炎症。我们在炎症性肠病硫酸钠模型中的新数据表明，P-2负责引起炎症反应，从而提供了对IBD发病机理的新见解，这对于为克罗恩病开发治疗方案可能很重要。此外，P-2在抗菌防御中的作用为抗抗生素耐药细菌感染提供了机会。在应用程序中，我们将以三个特定目标进行工作。在第一个目的中，我们将研究P-2的粘膜免疫力足够和P-2缺乏小鼠对胃鼠伤寒的胃感染，并确定炎症反应与P-2有关的作用和分子机制。在第二个特定目的中，我们将研究P-2在腹泻诱导中的作用在硫酸钠疾病模型中（DSS）和P-2在微生物组组成中的作用。在第三个特定目的中，将研究P-2缺陷小鼠对甲氧西林抗甲氧西林金黄色葡萄球菌（MRSA）的敏感性，并研究了正在研究的角质形成细胞中P-2介导的MRSA杀死的分子机制。