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

• 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
• 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

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 炎性症是多动蛋白复合物，可作为胞质传感器。因此，他们回应 内源性和外源性产生的细胞代谢和完整性的妥协和改变 “与危险相关的刺激”。相反，异常和慢性炎性体激活可能有助于 自发疾病。炎性体复合物的组装导致胱天蛋白酶自动激活， IL-1β和IL-18的问题，通常是凋亡细胞死亡。虽然有一个下游的共同点 炎性体激活后的事件，响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，以及我们对个人贡献的理解 对许多对环境挑战的先天免疫反应的炎症已被收集到 从缺乏各种NLR的小鼠线的研究中。相比之下，有关 对两种炎症的免疫调查的贡献，这是该提案的重点：NLRP1和 卡8。缺乏有关这两个相关炎症的信息的主要因素是有限的可用性 动物模型以评估人类炎症体的功能。功能的主要差异 人和小鼠NLRP1是由NLRP1蛋白结构和表达的物种差异提出的 图案。在Card8的情况下，在该蛋白质上分配给该蛋白的功能的体内验证已是 在小鼠/啮齿动物中不可能，因为这些物种不存在基因。那，对这个炎症组的研究 使用人细胞系和组织几乎完全取决于体外和实体研究。我们建议 通过使用同步替换来生成表达新颖的鼠标线条，以解决我们知识的差距 人NLRP1和Card8。