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
基本信息
- 批准号:9032916
- 负责人:
- 金额:--
- 依托单位:
- 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:2016-01-01 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:Alternative SplicingApoptosisAstrocytesBenignBinding SitesBiologyBrainCREB1 geneCellsChildChronicCodeComorbidityComplexDNADNA analysisDataDevelopmentDiabetes MellitusDiagnosisDiseaseExonsExperimental Autoimmune EncephalomyelitisFDA approvedFRAP1 geneFamilyFamily memberFemaleGenesGeneticGenomicsGulf WarHLA AntigensHigh PrevalenceHumanIn VitroInduction of ApoptosisInflammationInflammatoryInflammatory ResponseIntronsKnock-outLeadLoxP-flanked alleleMessenger RNAMetabolismMetforminMilitary PersonnelMusMutationNeurogliaNucleotidesOdds RatioOligodendrogliaOther GeneticsOvarian CystsParentsPathogenesisPatientsPeripheralPeutz-Jeghers SyndromePharmaceutical PreparationsPhenotypePhosphotransferasesPopulationPrevalenceProductionProtein BiosynthesisProtein KinaseProtein-Serine-Threonine KinasesRaceRecruitment ActivityRelapseReportingRiskRisk FactorsRoleSTK11 geneSamplingScaffolding ProteinSequence AnalysisSiblingsSingle Nucleotide PolymorphismSpinal CordSyndromeT-Cell ActivationT-LymphocyteTestingTherapeuticTumor Suppressor GenesVariantVeteransadenylate kinasecell growthcell growth regulationcohortcytokinegenetic risk factorgenome wide association studyindexingmembermouse modelmultiple sclerosis patientnovelpromoterpublic health relevanceresponsescreeningthymocytetranscription factortumor
项目摘要
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MS患者进行PBMC研究的过程中,鉴定了一个具有5个兄弟姐妹诊断为MS的家庭。MS在美国的患病率约为1:1000,有5个兄弟姐妹患有MS的几率极低,尚未报道。某些罕见肿瘤的合并症的存在导致了肿瘤抑制基因STK 11的测序分析,并在内含子V中鉴定出突变。STK 11编码LKB 1激酶,其涉及T细胞中的细胞代谢和炎症反应、神经胶质细胞中的炎症反应以及少突胶质细胞成熟的调节。这导致了我们的假设,即STK 11基因突变导致LKB 1表达减少,导致MS患者T细胞活化增加,这有助于MS表型的发展。由于LKB 1在MS中的作用尚未得到表征,我们进一步假设LKB 1表达或活性的变化发生在EAE(MS的小鼠模型)的过程中。如果是这样,那么增加LKB 1的治疗可能具有治疗益处。在这个项目中,我们将确定索引家族的其他成员是否在STK 11基因中具有相同或相似的突变;并测试从这些家族成员中分离的PBMC具有LKB 1 mRNA表达减少或改变以及T细胞活化增加的假设。由于单独的STK 11突变不足以诱导MS型表型,我们将进行完整的外显子组和基因组测序以鉴定与STK 11突变一起可能导致MS的相关变体。我们将通过对来自3,000名MS患者(复发缓解型和原发进展型)和匹配的对照,包括从海湾战争时期服役的不同种族退伍军人中获得的样品。使用人类T细胞,我们将确定STK 11突变如何影响T细胞活化;然后通过实验操作LKB 1表达以确定对T细胞活化的影响。在最初的研究中,我们发现减少星形胶质细胞的LKB 1会增加其炎症反应,因此我们将在体外表征星形胶质细胞中的LKB 1,并确定操纵LKB 1是否会改变星形胶质细胞的反应。在小鼠中,我们将确定在EAE过程中LKB 1的表达是否在脑、脊髓和外周T细胞中发生变化。使用LKB 1 floxed小鼠,我们将测试从T细胞或星形胶质细胞中条件性敲除LKB 1是否会导致或加剧EAE疾病。最后,我们将测试二甲双胍,一种FDA批准的治疗糖尿病的药物,是否可以在体外选择性诱导LKB 1缺陷T细胞的凋亡。阳性结果将证明LKB 1在MS疾病发展中的新作用,并表明二甲双胍或相关药物可用于减少T细胞LKB 1表达缺陷的MS患者中的活化T细胞。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Douglas L. Feinstein其他文献
Effect of pioglitazone treatment in a patient with secondary multiple sclerosis
吡格列酮治疗继发性多发性硬化症患者的效果
- DOI:
- 发表时间:
2004 - 期刊:
- 影响因子:9.3
- 作者:
H. Pershadsingh;M. Heneka;Rashmi Saini;Navin M Amin;Daniel J Broeske;Douglas L. Feinstein - 通讯作者:
Douglas L. Feinstein
Protection of focal ischemic infarction by rilmenidine in the animal: evidence that interactions with central imidazoline receptors may be neuroprotective.
利美尼定对动物局部缺血性梗塞的保护作用:与中枢咪唑啉受体相互作用的证据可能具有神经保护作用。
- DOI:
10.1016/0002-9149(94)90038-8 - 发表时间:
1994 - 期刊:
- 影响因子:0
- 作者:
Donald J. Reis;S. Regunathan;E. Golanov;Douglas L. Feinstein - 通讯作者:
Douglas L. Feinstein
Transient expression of calcium‐independent nitric oxide synthase in blood vessels during brain development
大脑发育过程中血管中钙依赖性一氧化氮合酶的瞬时表达
- DOI:
10.1096/fasebj.9.15.8529843 - 发表时间:
1995 - 期刊:
- 影响因子:0
- 作者:
E. Galea;Donald J. Reis;Hu1 Xu;Douglas L. Feinstein - 通讯作者:
Douglas L. Feinstein
Neuroinflammation in Alzheimer disease
阿尔茨海默病中的神经炎症
- DOI:
10.1038/s41577-024-01104-7 - 发表时间:
2024-12-09 - 期刊:
- 影响因子:60.900
- 作者:
Michael T. Heneka;Wiesje M. van der Flier;Frank Jessen;Jeroen Hoozemanns;Dietmar Rudolf Thal;Delphine Boche;Frederic Brosseron;Charlotte Teunissen;Henrik Zetterberg;Andreas H. Jacobs;Paul Edison;Alfredo Ramirez;Carlos Cruchaga;Jean-Charles Lambert;Agustin Ruiz Laza;Jose Vicente Sanchez-Mut;Andre Fischer;Sergio Castro-Gomez;Thor D. Stein;Luca Kleineidam;Michael Wagner;Jonas J. Neher;Colm Cunningham;Sim K. Singhrao;Marco Prinz;Christopher K. Glass;Johannes C. M. Schlachetzki;Oleg Butovsky;Kilian Kleemann;Philip L. De Jaeger;Hannah Scheiblich;Guy C. Brown;Gary Landreth;Miguel Moutinho;Jaime Grutzendler;Diego Gomez-Nicola;Róisín M. McManus;Katrin Andreasson;Christina Ising;Deniz Karabag;Darren J. Baker;Shane A. Liddelow;Alexei Verkhratsky;Malu Tansey;Alon Monsonego;Ludwig Aigner;Guillaume Dorothée;Klaus-Armin Nave;Mikael Simons;Gabriela Constantin;Neta Rosenzweig;Alberto Pascual;Gabor C. Petzold;Jonathan Kipnis;Carmen Venegas;Marco Colonna;Jochen Walter;Andrea J. Tenner;M. Kerry O’Banion;Joern R. Steinert;Douglas L. Feinstein;Magdalena Sastre;Kiran Bhaskar;Soyon Hong;Dorothy P. Schafer;Todd Golde;Richard M. Ransohoff;David Morgan;John Breitner;Renzo Mancuso;Sean-Patrick Riechers - 通讯作者:
Sean-Patrick Riechers
Cardiac Depression Induced by Cocaine or Cocaethylene are Alleviated by Lipid Emulsion More Effectively Than by Sulfobutylether β -Cyclodextrin
脂质乳剂比磺丁基醚 β-环糊精更能有效地缓解可卡因或可卡乙烯引起的心脏抑制
- DOI:
- 发表时间:
2015 - 期刊:
- 影响因子:0
- 作者:
Michael R. Fettiplace;A. Pichurko;Richard Ripper;Bocheng Lin;Katarzyna Kowal;K. Lis;David E. Schwartz;Douglas L. Feinstein;Israel;Rubinstein;Guy L. Weinberg - 通讯作者:
Guy L. Weinberg
Douglas L. Feinstein的其他文献
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{{ truncateString('Douglas L. Feinstein', 18)}}的其他基金
Optimization of Bile Sequestrants to Treat Superwarfarin Poisoning
治疗超级华法林中毒的胆汁螯合剂的优化
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Accelerating remyelination using lanthionine ketimine derivatives
使用羊毛硫氨酸酮亚胺衍生物加速髓鞘再生
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10708047 - 财政年份:2022
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Accelerating remyelination using lanthionine ketimine derivatives
使用羊毛硫氨酸酮亚胺衍生物加速髓鞘再生
- 批准号:
10539555 - 财政年份:2022
- 资助金额:
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Characterization of the oral microbiome of patients with Multiple Sclerosis
多发性硬化症患者口腔微生物组的特征
- 批准号:
10484039 - 财政年份:2022
- 资助金额:
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Liver Kinase B1, a genetic risk factor for multiple sclerosis
肝激酶 B1,多发性硬化症的遗传危险因素
- 批准号:
9891886 - 财政年份:2016
- 资助金额:
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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:
9206882 - 财政年份:2016
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Liver Kinase B1, a genetic risk factor for multiple sclerosis
肝激酶 B1,多发性硬化症的遗传危险因素
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