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.
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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Douglas L. Feinstein', 18)}}的其他基金
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:
10708047 - 财政年份:2022
- 资助金额:
-- - 项目类别:
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
- 批准号:
10707127 - 财政年份:2022
- 资助金额:
-- - 项目类别:
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:
-- - 项目类别:
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:
-- - 项目类别:
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:
-- - 项目类别:
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
- 资助金额:
-- - 项目类别:
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:
10427134 - 财政年份:2016
- 资助金额:
-- - 项目类别:
相似国自然基金
Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
- 批准号:LBY21H010001
- 批准年份:2020
- 资助金额:0.0 万元
- 项目类别:省市级项目
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
- 批准号:81703335
- 批准年份:2017
- 资助金额:20.0 万元
- 项目类别:青年科学基金项目
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
- 批准号:81670594
- 批准年份:2016
- 资助金额:58.0 万元
- 项目类别:面上项目
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
- 批准号:81470791
- 批准年份:2014
- 资助金额:73.0 万元
- 项目类别:面上项目
Apoptosis signal-regulating kinase 1是七氟烷抑制小胶质细胞活化的关键分子靶点?
- 批准号:81301123
- 批准年份:2013
- 资助金额:23.0 万元
- 项目类别:青年科学基金项目
APO-miR(multi-targeting apoptosis-regulatory miRNA)在前列腺癌中的表达和作用
- 批准号:81101529
- 批准年份:2011
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
放疗与细胞程序性死亡(APOPTOSIS)相关性及其应用研究
- 批准号:39500043
- 批准年份:1995
- 资助金额:9.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Development of an apoptosis biosensor for monitoring of breast cancer
开发用于监测乳腺癌的细胞凋亡生物传感器
- 批准号:
10719415 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Milk fat globule-EGF factor 8 and hepatocyte apoptosis-induced liver wound healing response
乳脂肪球-EGF因子8与肝细胞凋亡诱导的肝脏创面愈合反应
- 批准号:
10585802 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Interrogating the Fgl2-FcγRIIB axis on CD8+ T cells: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells
询问 CD8 T 细胞上的 Fgl2-FcγRIIB 轴:介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制
- 批准号:
10605856 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Mechanistic analysis of apoptosis induction by HDAC inhibitors in head and neck cancer
HDAC抑制剂诱导头颈癌凋亡的机制分析
- 批准号:
23K15866 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Early-Career Scientists
Novel targeted therapy for FGFR inhibitor-resistant urothelial cancer and apoptosis based therapy for urothelial cancer
FGFR抑制剂耐药性尿路上皮癌的新型靶向治疗和基于细胞凋亡的尿路上皮癌治疗
- 批准号:
23K08773 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Interrogating the Fgl2-FcgRIIB axis: A novel mechanism mediating apoptosis of tumor-specific memory CD8+ T cells
探究 Fgl2-FcgRIIB 轴:介导肿瘤特异性记忆 CD8 T 细胞凋亡的新机制
- 批准号:
10743485 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Investigating the role of apoptosis-resistance and the tumor environment on development and maintenance of sacrococcygeal teratomas
研究细胞凋亡抗性和肿瘤环境对骶尾部畸胎瘤发生和维持的作用
- 批准号:
10749797 - 财政年份:2023
- 资助金额:
-- - 项目类别:
The effects of glucose on immune cell apoptosis and mitochondrial membrane potential and the analysis of its mechanism by which glucose might modulate the immune functions.
葡萄糖对免疫细胞凋亡和线粒体膜电位的影响及其调节免疫功能的机制分析。
- 批准号:
22K09076 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
XAF1 IN P53 SIGNALING, APOPTOSIS AND TUMOR SUPPRESSION
P53 信号传导、细胞凋亡和肿瘤抑制中的 XAF1
- 批准号:
10583516 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Role of Thioredoxin system in regulation of autophagy-apoptosis cross talk in neurons: Uncovering Novel Molecular Interactions.
硫氧还蛋白系统在神经元自噬-凋亡串扰调节中的作用:揭示新的分子相互作用。
- 批准号:
RGPIN-2019-05371 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Discovery Grants Program - Individual














{{item.name}}会员




