Identification and characterization of a novel risk factor for MS

多发性硬化症新危险因素的鉴定和表征

• 批准号: 9032916
• 负责人: Douglas L. Feinstein
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032916
• 关键词: Alternative Splicing; Apoptosis; Astrocytes; Benign; Binding Sites; Biology; Brain; CREB1 gene; Cells; Child; Chronic; Code; Comorbidity; Complex; DNA; DNA analysis; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Exons; Experimental Autoimmune Encephalomyelitis; FDA approved; FRAP1 gene; Family; Family member; Female; Genes; Genetic; Genomics; Gulf War; HLA Antigens; High Prevalence; Human; In Vitro; Induction of Apoptosis; Inflammation; Inflammatory; Inflammatory Response; Introns; Knock-out; Lead; LoxP-flanked allele; Messenger RNA; Metabolism; Metformin; Military Personnel; Mus; Mutation; Neuroglia; Nucleotides; Odds Ratio; Oligodendroglia; Other Genetics; Ovarian Cysts; Parents; Pathogenesis; Patients; Peripheral; Peutz-Jeghers Syndrome; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Population; Prevalence; Production; Protein Biosynthesis; Protein Kinase; Protein-Serine-Threonine Kinases; Race; Recruitment Activity; Relapse; Reporting; Risk; Risk Factors; Role; STK11 gene; Sampling; Scaffolding Protein; Sequence Analysis; Siblings; Single Nucleotide Polymorphism; Spinal Cord; Syndrome; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tumor Suppressor Genes; Variant; Veterans; adenylate kinase; cell growth; cell growth regulation; cohort; cytokine; genetic risk factor; genome wide association study; indexing; member; mouse model; multiple sclerosis patient; novel; promoter; public health relevance; response; screening; thymocyte; transcription factor; tumor

 DESCRIPTION (provided by applicant): During the course of recruiting MS patients for a study of PBMCs, a family with 5 siblings diagnosed with MS was identified. The prevalence of MS in the US is roughly 1:1000, the odds of having 5 siblings with MS is extremely low and has not been reported. The presence of comorbidity for certain rare tumors led to sequencing analysis of tumor suppressor gene STK11, and a mutation was identified in intron V. STK11 codes for the LKB1 kinase which has been implicated in regulation of cellular metabolism and inflammatory responses in T cells, of inflammatory responses in glial cells, and in oligodendrocyte maturation. This leads to our hypothesis that mutations in STK11 gene leading to a reduction in LKB1 expression cause increased activation of T cells in MS patients which contributes to development of an MS phenotype. Since the role of LKB1 in MS has not been characterized, we further hypothesize that changes in LKB1 expression or activity occur during the course of EAE, the mouse model of MS. If so, then treatments to increase LKB1 may be of therapeutic benefit. In this project, we will determine if other members of the index family harbor the same or similar mutation in the STK11 gene; and test the hypothesis that PBMCs isolated from these family members have reduced or altered expression of LKB1 mRNA, and increased T cell activation. Since a mutation in STK11 alone is not sufficient to induce an MS type phenotype we will carry out full exomic and genomic sequencing to identify associated variants which together with the STK11 mutation could lead to MS. We will determine if the prevalence of any novel variants are increased in the MS population by PCR analysis of DNA samples from 3,000 MS patients (both relapsing remitting and primary progressive forms) and matched controls, including samples obtained from military Veterans of different races who served in the Gulf War Era. Using human T cells, we will determine how the STK11 mutation influences T cell activation; then experimentally manipulate LKB1 expression to identify effects on Tcell activation. In initial studies we found tha reducing LKB1 from astrocytes increase their inflammatory responses, we will therefore characterize LKB1 in astrocyte in vitro and determine if manipulating LKB1 alters astrocyte responses. In mice, we will determine if expression of LKB1 changes during the course of EAE in brain, spinal cord, and in peripheral T cells. Using an LKB1 floxed mouse, we will test if conditional knockout of LKB1 from T cells or astrocytes leads to or exacerbates EAE disease. Finally, we will test if metformin, an FDA approved drug to treat diabetes, can selectively induce apoptosis in the LKB1 deficient T cells in vitro. Positive findings will demonstrate a novel role fr LKB1 in the development of MS disease, and suggest that metformin or related drugs could be used to reduce activated T cells in MS patients who have deficiencies in Tcell LKB1 expression.

 描述（由申请人提供）： 在招募PBMC的过程中，MS的公主大约是1：1000。肿瘤倡导者基因STK11的内含子V。STK11代码在T细胞中循环的LKB1激酶，在常规代谢和炎症反应中，神经胶质细胞中的炎症反应会导致少突胶质细胞成熟。由于LKB1在MS模型中的表征，MS患者的T型有助于MS表型。将在STK11基因中确定Samily的相同或相似的突变；从家族成员中分离出来的CS会减少或改变LKB1 mRNA的表达，并增加了T CEL的作用。完整的例外测序以识别与STK11突变一起的变体可能导致女士。我们将通过对3000毫秒患者ED对照组的DNA样品的PCR分析（包括获得采样采样取样）的DNA样品来确定MS种群中Ayny新颖的变体的患病率是否增加在海湾战争时代的不同种族的退伍军人中，我们将确定STK11突变在最初的研究中如何影响T细胞的激活。如果在小鼠中操纵LKB1星形胶质细胞反应。或加剧EAE疾病。在TCELL LKB1表达中具有CIE的MS患者中，药物可以用作活化助剂的T细胞。