Mucosal Immune Checkpoints in Chronic Bacterial Cystitis

慢性细菌性膀胱炎的粘膜免疫检查点

• 批准号: 7712858
• 负责人: THOMAS Joseph HANNAN
• 金额: $ 11.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7712858
• 关键词: Acute; Address; Adolescent; Adult; Affect; Age; Allergic; Antibiotic Therapy; Antibodies; Bacteria; Bacteriuria; Biological Assay; Bladder; Bone Marrow; C3H/HeN Mouse; Cells; Chronic; Chronic Cystitis; Chronic Inflammatory Infiltrate; Clinical; Collaborations; Colony-Stimulating Factors; Communicable Diseases; Core Facility; Cystitis; Development; Disease; Disease Outcome; Doctor of Philosophy; Epithelium; Escherichia coli Infections; Etiology; Face; Fellowship; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Growth and Development function; Health Care Costs; Host Defense; Hour; Human; IL8 gene; Immune; Immune response; Immunodeficient Mouse; Immunoglobulins; Immunology; Inbred C3H Mice; Infection; Infectious Diseases Research; Infective cystitis; Inflammation; Inflammatory; Inflammatory Response; Institution; Instruction; Interleukin-5; Interleukin-6; Joints; K-Series Research Career Programs; Kidney; Kinetics; Knowledge; Left; Lower urinary tract; Lymphocyte; Lymphoid Follicle; Marriage; Mediating; Mentors; Mentorship; Microbiology; Modeling; Molecular; Mouse Strains; Mus; Nature; Outcome; Pathogenesis; Pathology; Postdoctoral Fellow; Prevalence; Principal Investigator; Production; Pyuria; Reaction; Recording of previous events; Recurrence; Reporter; Research; Research Personnel; Research Proposals; Resistance; Resolution; Respiratory Burst; Role; Serum; Signal Transduction; Site; Staining method; Stains; Suspension substance; Suspensions; T-Lymphocyte; Technical Expertise; Testing; Therapeutic; Tissues; Training; Transgenic Organisms; United States; Universities; Urinary tract; Urinary tract infection; Uropathogenic E. coli; Urothelium; Washington; Work; analog; base; cost; cytokine; granulocyte; immune function; interest; keratinocyte; killings; loss of function; mast cell; mouse model; neutrophil; pathogen; prophylactic; research study; response; therapeutic vaccine; Acute; Address; Adolescent; Adult; Affect; Age; Allergic; Antibiotic Therapy; Antibodies; Bacteria; Bacteriuria; Biological Assay; Bladder; Bone Marrow; C3H/HeN Mouse; Cells; Chronic; Chronic Cystitis; Chronic Inflammatory Infiltrate; Clinical; Collaborations; Colony-Stimulating Factors; Communicable Diseases; Core Facility; Cystitis; Development; Disease; Disease Outcome; Doctor of Philosophy; Epithelium; Escherichia coli Infections; Etiology; Face; Fellowship; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Growth and Development function; Health Care Costs; Host Defense; Hour; Human; IL8 gene; Immune; Immune response; Immunodeficient Mouse; Immunoglobulins; Immunology; Inbred C3H Mice; Infection; Infectious Diseases Research; Infective cystitis; Inflammation; Inflammatory; Inflammatory Response; Institution; Instruction; Interleukin-5; Interleukin-6; Joints; K-Series Research Career Programs; Kidney; Kinetics; Knowledge; Left; Lower urinary tract; Lymphocyte; Lymphoid Follicle; Marriage; Mediating; Mentors; Mentorship; Microbiology; Modeling; Molecular; Mouse Strains; Mus; Nature; Outcome; Pathogenesis; Pathology; Postdoctoral Fellow; Prevalence; Principal Investigator; Production; Pyuria; Reaction; Recording of previous events; Recurrence; Reporter; Research; Research Personnel; Research Proposals; Resistance; Resolution; Respiratory Burst; Role; Serum; Signal Transduction; Site; Staining method; Stains; Suspension substance; Suspensions; T-Lymphocyte; Technical Expertise; Testing; Therapeutic; Tissues; Training; Transgenic Organisms; United States; Universities; Urinary tract; Urinary tract infection; Uropathogenic E. coli; Urothelium; Washington; Work; analog; base; cost; cytokine; granulocyte; immune function; interest; keratinocyte; killings; loss of function; mast cell; mouse model; neutrophil; pathogen; prophylactic; research study; response; therapeutic vaccine

DESCRIPTION (provided by applicant): In this application, I am requesting career development award support to investigate "Mucosal Immune Checkpoints in Chronic Bacterial Cystitis." I will be undertaking this work in collaboration with my co-mentors, Marco Colonna and Scott Hultgren, both here at Washington University. This marriage of these experts in the fields of Immunology and Microbiology will serve as a great mentoring team as I embark on this joint post- doctoral fellowship. This collaboration arose out of my interest in a murine model of chronic bacterial cystitis. Urinary tract infections (UTI) are common, costly, and very often recurrent. Uropathogenic E. coli (UPEC) are the most common cause of UTI. UPEC elicit host defenses in response to colonization. Understanding the role of the host response in this disease is critical for our ability to develop effective vaccines and therapeutics. We have found that juvenile C3H/HeN mice have two distinct responses to UPEC infection: either they resolve infection within 2 weeks or they develop chronic cystitis that lasts for at least 7 months. Furthermore, development of chronic cystitis strongly correlates with a significantly more severe acute host response. This allergic-like response, which is not seen in other mouse strains studied, forms the basis for the hypothesis of this study, which is that there is a host checkpoint that is being triggered prior to the development of chronic cystitis. This study will test this hypothesis by investigate the cellular and molecular mechanism of this checkpoint and testing for causality. Dr. Colonna will be providing mentorship, knowledge and technical expertise during this project as I address these difficult questions. Dr. Hultgren will be providing mentorship and expertise in the field of infectious disease research and the murine model of UTI. Washington University is a wonderful place to pursue scientific research, with numerous support and core facilities. Upon leaving clinical veterinary practice in 2003, I began my doctoral training with Dr. Hultgren and graduated with a Ph.D. in Microbiology in August, 2008. I became interested in host responses to infection towards the end of my graduate work and decided to pursue a post-doctoral fellowship in Immunology to broaden my expertise in mechanisms of infectious disease. I hope to work at an academic research institution as an independent investigator studying the host-pathogen interaction. RELEVANCE (See instructions): Urinary tract infections (UTI) are a major problem: they are common, costly, and often recurrent or chronic. We have developed a mouse model of chronic urinary tract infection with the bacterium uropathogenic E. coli, and found that development of chronic infection is associated with an allergic-like bladder response early in infection. After having this reaction, these mice are prone to recurrent UTI, providing a possible explanation for recurrent UTI in humans.

描述（由申请人提供）：在本申请中，我要求职业发展奖支持，以调查“慢性细菌膀胱炎中的粘膜免疫检查点”。我将与华盛顿大学的Marco Colonna和Scott Hultgren合作进行这项工作。这些专家在免疫学和微生物学领域的婚姻将成为一支伟大的指导团队，因为我开始了这一联合博士后研究金。这种合作源于我对慢性细菌膀胱炎的鼠模型的兴趣。尿路感染（UTI）是常见的，昂贵的，而且经常经常发生。肝病大肠杆菌（UPEC）是UTI的最常见原因。 UPEC响应殖民化引起宿主防御。了解宿主反应在这种疾病中的作用对于我们开发有效的疫苗和治疗剂的能力至关重要。我们发现，少年C3H/母鸡对UPEC感染有两种不同的反应：它们要么在2周内解决感染，要么患有慢性膀胱炎，持续至少7个月。此外，慢性膀胱炎的发展与更严重的急性宿主反应密切相关。这种过敏反应在研究的其他小鼠菌株中未见，构成了这项研究假设的基础，即在慢性膀胱炎发展之前，有一个宿主检查点正在触发。这项研究将通过研究该检查点的细胞和分子机制和因果关系测试来检验这一假设。 Colonna博士将在我解决这些困难的问题时提供指导，知识和技术专业知识。 Hultgren博士将在传染病研究领域和UTI鼠模型领域提供指导和专业知识。华盛顿大学是一个拥有众多支持和核心设施的科学研究的好地方。 2003年离开临床兽医实践后，我开始与霍尔格伦博士的博士培训，并获得了博士学位。我在2008年8月的微生物学上。我对我的研究生工作结束时对感染的宿主反应感兴趣，并决定寻求免疫学后奖学金，以扩大我在感染疾病机制方面的专业知识。我希望能在一家研究宿​​主病原体相互作用的独立研究人员工作。相关性（请参阅说明）：尿路感染（UTI）是一个主要问题：它们是常见，昂贵且经常发生或慢性病。我们已经开发了一种用细菌肝癌大肠杆菌的慢性尿路感染的小鼠模型，发现慢性感染的发展与感染早期的过敏性膀胱反应有关。反应后，这些小鼠容易复发UTI，为人类反复发作的UTI提供了可能的解释。