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：
10354472
负责人：
Beverly H Koller
金额：
$ 23.33万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10354472
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.

抽象的炎症小体是作为胞质传感器发挥作用的多蛋白复合物，因此它们对信号做出反应。内源性和外源性导致的细胞代谢和完整性的损害和改变 “与危险相关的刺激”可能导致离线、异常和慢性炎症体激活。炎症小体复合物的组装导致半胱天冬酶的自身激活， IL-1β 和 IL-18 的成熟，并且经常导致细胞焦亡，而下游存在共同点。炎症体激活后发生的事件，反应的特异性取决于种系编码由特定危险相关刺激触发的模式识别受体许多细胞传感器。例如 NLRP3 属于 NLR 基因家族，我们对个体的贡献有很多理解已收集到对多种环境挑战的先天免疫反应的炎症小体相比之下，关于缺乏各种 NLR 的小鼠品系的信息有限。本提案重点关注的两种炎症小体对免疫反应的贡献：NLRP1 和 CARD8. 缺乏这两种相关炎症小体信息的一个主要因素是其可用性有限。动物模型来评估人类炎症小体的功能的主要差异。 NLRP1 蛋白结构和表达的物种差异表明人类和小鼠 NLRP1 存在差异就 CARD8 而言，暂定分配给该蛋白质的功能的体内验证已经完成。在小鼠/啮齿类动物中这是不可能的，因为这些物种中不存在该基因，因此，对这种炎性体的研究。我们建议几乎完全依赖于使用人类细胞系和组织的体外和离体研究。通过利用同线性替换来产生表达的新小鼠品系，弥补了我们知识上的这一空白人类 NLRP1 和 CARD8。