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Mouse models for study of the NLRP1 and CARD8 inflammasomes

用于研究 NLRP1 和 CARD8 炎性体的小鼠模型

基本信息

批准号：
10493370
负责人：
Beverly H Koller
金额：
$ 19.44万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10493370
关键词：
129 Mouse Address Animal Model Autoimmune Diseases C-terminal Caspase Cell Death Cells Chronic Complex Development Disease Event Future Gene Family Generations Genes Glean Goals Host Defense Human Human Cell Line Human Genome Immune Immune response In Vitro Individual Inflammasome Inflammatory Innate Immune Response Interleukin-1 beta Interleukin-18 Knowledge Leucine-Rich Repeat Mediating Metabolism Modeling Molecular Multiprotein Complexes Mus N-terminal Orthologous Gene Pattern Pattern recognition receptor Population Positioning Attribute Process Protein Family Proteins Reporting Rodent Role Specificity Stimulus Structure Study models Tissues Validation Work autoinflammatory body system genetic manipulation in vivo innate immune pathways marenostrin microbial mouse genome mouse model multicatalytic endopeptidase complex novel polypeptide protein expression protein structure response sensor species difference tool

项目摘要

ABSTRACT Inflammasomes are multiprotein complexes that function as cytosolic sensors. As such, they respond to compromise and alteration of cellular metabolism and integrity resulting from both endogenous and exogenous “danger-associated stimuli”. Conversely, aberrant and chronic inflammasome activation can contribute to autoinflammatory diseases. Assembly of the inflammasome complex results in autoactivation of caspases, maturation of IL-1β and IL-18, and often pyroptotic cell death. While there is a downstream commonality in the events following inflammasome activation, the specificity of the response is dependent on germline-encoded pattern recognition receptors triggered by the specific danger-associated stimuli. Many of the cellular sensors such as NLRP3 belong to the NLR gene family, and much of our understanding of the contribution of individual inflammasomes to the innate immune responses to a plethora of environmental challenges has been gleaned from the study of mouse lines lacking various NLRs. In contrast, there is limited information regarding the contribution to immune responses of two inflammasomes that are the focus of this proposal: NLRP1 and CARD8. A major factor in the lack of information on these two related inflammasomes is the limited availability of animal models to evaluate the function of the human inflammasome. Major differences in the functions of human and mouse NLRP1 are suggested by species differences in NLRP1 protein structure and expression pattern. In the case of CARD8, in vivo validation of the functions tentatively assigned to this protein have been impossible in mice/rodents because the gene is absent in these species. Thus, the study of this inflammasome has depended almost entirely on in vitro and ex vivo studies using human cell lines and tissue. We propose to address this gap in our knowledge by utilizing syntenic replacement to generate novel mouse lines expressing human NLRP1 and CARD8.

摘要