权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of NLRC4 inflammasome-associated hyperinflammation

NLRC4炎症小体相关的过度炎症的机制

基本信息

批准号：
9087657
负责人：
Scott William Canna
金额：
$ 16.2万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087657
关键词：
Address American Anti-Inflammatory Agents Anti-inflammatory Biology CASP1 gene Cell Death Cells Cessation of life Chronic Collaborations Dangerousness Data Diagnosis Disease Epigenetic Process Epithelial Cells Exposure to Foundations Genetic Transcription Germ Lines Goals Histiocytosis Human Hyperactive behavior Immune Immune system Immunologics Infection Inflammasome Inflammation Inflammatory Inflammatory Response Inflammatory disease of the intestine Innate Immune Response Interferon Type II Interleukin-1 beta Interleukin-18 Intestines Knowledge Lead Life Link Lymphocyte Macrophage Activation Mendelian disorder Multiprotein Complexes Mus Mutation Natural Killer Cells Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Plant Roots Prevention Production Proteins Recurrence Risk Factors Role Sepsis Sepsis Syndrome Serum Signal Transduction Stimulus Stratification Syndrome Transgenic Mice Variant career cell type clinically relevant cytokine cytopenia early onset experimental study human disease infancy insight interleukin-18 binding protein intestinal epithelium macrophage novel prevent protein complex public health relevance response sensor targeted treatment tool training opportunity translational scientist treatment strategy working group

项目摘要

DESCRIPTION (provided by applicant): It has long been recognized that dysregulated inflammation causes many human diseases. The systemic inflammatory response, best associated with infections (termed sepsis), is a common and life- threatening example of hyperinflammatory damage. Very little is known about what regulates an appropriate versus excessive inflammatory response, or how to manipulate inflammation to prevent damage. The goal of this proposal is to understand how mutations in a protein called NLRC4 result in a human sepsis-like phenotype known as Macrophage Activation Syndrome (MAS). When activated, NLRC4 triggers the formation of a large protein complex called the inflammasome. Inflammasomes drive inflammation throughout the body by activating pro-inflammatory cytokines and inducing an inflammatory form of cell death. Intriguingly, in addition to MAS, NLRC4 mutations cause early-onset intestinal inflammation that resolves in infancy. How these mutations result in this specific hyperinflammatory syndrome is unknown. Understanding this mechanism will provide important insights into basic inflammasome function, the risk factors for hyperinflammatory damage, the different immunologic "flavors" of systemic inflammation, and the ways we might intervene to prevent damage. Aim 1 of this proposal will examine the mechanisms by which NLRC4 mutations cause inflammatory damage. To facilitate this, NLRC4 mutations will be compared to mutations in a related inflammasome component called NLRP3. NLRP3 hyperactivity also causes inflammasome formation, but a very different inflammatory syndrome. This aim will focus on how these different inflammasomes function in the same cell type, as well as the systemic effects of which cells have active inflammasomes. The unique role of inflammasomes in intestinal epithelial cells may inform the transient gut phenotype unique to NLRC4-MAS. Aim 2 will explore an important but enigmatic finding: extraordinary and chronic elevation of the inflammasome- dependent cytokine IL-18 occurs in MAS (regardless of NLRC4 mutations) but not NLRP3-related diseases. This aim will examine how chronic exposure to high IL-18 primes the immune system for an MAS-like response to danger signals, looking both systemically and in-depth at IL-18 responsive cells. Completion of these aims, along with the training opportunities included as part of this proposal, will establish the necessary foundation for a career as an independent translational investigator.