Development of mouse models for autoinflammatory rare diseases

自身炎症性罕见疾病小鼠模型的开发

基本信息

批准号：
9265977
负责人：
Do-Hyung Kim
金额：
$ 18.15万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265977
关键词：
3T3-L1 Cells Address Adipocytes Adipose tissue Affect Animal Model Anti-Bacterial Agents Antigen Presentation Antiviral Agents Asians Autoimmune Diseases Body fat Catalytic Domain Categories Cells Chronic Colitis Contracture Defect Disease European Excision Fasting Fatty acid glycerol esters Functional disorder Gene Targeting Genes Genetic Goals Grant Health Human Immune Immune response Impairment Inflammation Inflammatory Joints Knockout Mice Link Lipodystrophy Malignant Neoplasms Metabolic Metabolic Diseases Mus Muscle Muscular Atrophy Mutate Mutation Neurodegenerative Disorders Oligonucleotides Oxides Panniculitis Patients Pharmaceutical Preparations Phenotype Physiological Play Point Mutation Population Process Proteins Rare Diseases Reporting Resources Rheumatoid Arthritis Role Signal Transduction Stress Symptoms Syndrome System Techniques Therapeutic Tissues United States Virus Diseases adipocyte differentiation autoinflammatory blood glucose regulation bone cell type cytokine disability disease phenotype disease-causing mutation drug development exome sequencing gene product human disease insight knock-down lipid biosynthesis macrophage microcytic anemia model development mouse development mouse genome mouse model multicatalytic endopeptidase complex novel public health relevance response therapeutic development therapeutic target therapy development

项目摘要

DESCRIPTION (provided by applicant): Immunoproteasomes (i-proteasomes) are an inducible type of proteasomes that have proteolytic activities different from standard proteasomes. They play important roles not only in antigen presentation but also in removal of oxidized proteins that accumulate in stress. They also regulate cell signaling, inflammation and cytokine secretion in a variety of cell types. Recent homozygosity mapping and exome sequencing analysis revealed that one of the i-proteasomal beta subunits, LMP7 (Psmb8 gene product), is mutated in multiple autoinflammatory rare diseases, such as Nakajo-Nishimura syndrome (amyotrophy-fat tissue anomaly), CANDLE syndrome, and an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. There are multiple point mutations of LMP7 identified in European, United States and Asian populations that show similar disease phenotypes. A common feature of the diseases is deformation and dys-function of fat tissue along with problems in other tissues, such as bone and muscle. Although such a point mutation could cause problems, it is critical to recapitulate the disease conditions using mouse models to address whether or how the mutations cause the disease states. Our preliminary study showed that LMP7 deficiency suppresses fat accumulation in the body and fat mobilization in response to fasting and impairs glucose homeostasis. We also found that LMP7 knockdown suppresses adipogenesis in 3T3-L1 cells. Although the preliminary results greatly contributed to our understanding of the function of LMP7 in the disease-related phenotypes, the KO mice are not seen ideal to recapitulate the human disease conditions. The objective of this grant is to establish mouse models that can closely recapitulate the autoinflammatory rare syndromes caused by LMP7 mutation. The genetic mouse models reproducing the disease mutation will be important to decipher disease mechanisms and for development of therapeutic interventions. We will generate mice that harbor a point mutation Thr75Met in LMP7. We will use TALEN-assisted gene targeting technique combined with a donor oligonucleotide to introduce the point mutation into the mouse genome. We demonstrated that T75M mutation is critical for adipocyte differentiation and the i-proteasomal activity in 3T3-L1 adipocytes, indicating that T75M mutation has functional and phenotypic impact in murine cells. To further decipher the pathophysiology of the diseases, we will also use a tissue-specific mouse model and determine the roles of i-proteasomes in macrophages and adipocytes, the two major cell types residing in adipose tissue, in the disease phenotypes. For this, we have already made LMP7 flox mice. The mouse models are unique resources that will greatly contribute to understanding the pathophysiology of the rare diseases. They will also be useful to explore many human diseases belonging to the categories of autoimmune diseases as well as metabolic diseases, cancer and neurodegenerative diseases. They will be essential for therapeutic drug development for the rare diseases.

描述（由申请人证明）：免疫蛋白酶（I-Printeasoms）是一种可诱导的蛋白酶体类型，具有蛋白水解活性授生的毒素，从标准的蛋白酶体中，它们在诱导中也不重要，但也可以去除氧化蛋白在多种细胞类型中调节细胞信号，炎症和细胞因子。肌萎缩症组织异常），通过关节染色，肌肉萎缩，微细胞性贫血和panniculinitis诱发的脂质营养不良的糖果综合征。和肌肉。在3T3-L1细胞中。具有解密机制的突变和带有LMP7点突变的畸线干预措施。以及3T3-L1脂肪的I----脂质细胞中的I-Proboteasomal活性，在鼠细胞中的功能和表型。在疾病的表型中，我们的两种主要细胞类型，我们的rady使LMP7 flox小鼠有助于理解稀有的疾病。自身免疫性疾病作为代谢性疾病，癌症和神经退行性疾病。