Role of Leptin in murine modeles of IBD
瘦素在 IBD 小鼠模型中的作用
基本信息
- 批准号:7277821
- 负责人:
- 金额:$ 29.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-09-30 至 2009-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdenovirusesAffectBiopsyBone MarrowCell NucleusCellsChimera organismChronicColitisCrohn&aposs diseaseDataDevelopmentEatingEnergy MetabolismEpithelial CellsFood Intake RegulationGoalsHematopoieticHormonesHypothalamic structureImmuneImmunityImmunohistochemistryIn VitroInflammationInflammatoryInflammatory ResponseInflammatory disease of the intestineInjection of therapeutic agentInterleukin-10IntestinesLeptinLeptin deficiencyLymphocyte ActivationMediatingMesenteryMetabolicModelingMucous MembraneMusNeuronsOral AdministrationPathogenesisPatientsPopulationPredispositionProductionRectal AdministrationRegulationRelative (related person)Research PersonnelResistanceRoleRole playing therapySCID MiceSiteSodium Dextran SulfateSulfonic AcidsT-LymphocyteTimeTissuesTransplantationTrinitrobenzenesUlcerative ColitisWeightWorkautocrinecytokinedb/db mousein vivoleptin receptorlymph nodesparacrineprotective effectreceptorrecombinaseresponsevector
项目摘要
DESCRIPTION (provided by applicant): The goal of this project is to investigate the mechanisms by which leptin deficiency regulates susceptibility to intestinal inflammation in mice. In addition to act as a regulator of food intake and energy expenditure, leptin also modulates the immune and inflammatory response. Preliminary data indicate that leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice are resistant to colitis induced by chronic administration of DSS or TNBS. The current application will attempt to identify the cell populations responsible for the observed effects. In Specific Aim 1, to evaluate the relative role played by neuronal leptin receptors (Ob-R) in regulation of intestinal inflammation. DSS and TNBS will be administered to mice with a selective deficiency of Ob-R in neurons and their response compared with that of WF mice. To analyze in more detail the role of hypothalamic Ob-R, DSS- and TNBS-induced intestinal inflammation will be studied in mice in which Ob-R have been specifically deleted in the arcuate and ventromedial nuclei of the hypothalamus by injecting a vector expressing cre recombinase into Ob-Rflox/flox mice. Because the effects of leptin on both bone marrow- and non-bone marrow-derived cells could contribute to modulation of colitis in the models of DSS and TNBS administration, in Specific Aim 2 the relative contribution of Ob-R expression in these two cell populations will be investigated using bone marrow chimeras for Ob-R. WT bone marrow will be transplanted into db/db mice, while WT mice will receive db/db bone marrow and colitis development will be studied. Furthermore, the direct effects of leptin on T lymphocytes . Preliminary data indicate that Ob-R expression on donor T lymphocytes regulates induction of colitis in the model of CD4+ CD45RBhigh cells transfer into SCID mice. The transfer model will be employed in the attempt to dissect the relative role played by Ob-R expression in donor T lymphocytes versus cells in the recipient mouse. To investigate the direct role of Ob-R expression in T lymphocytes in the modulation of colitis induced by DSS or TNBS, mice with a selective deletion of Ob-R in T lymphocytes will be employed. Finally, in Specific Aim 3 production of leptin by immune cells at the site of intestinal inflammation will be evaluated in murine models and in biopsies of patients with IBD. The possible participation of immune-derived leptin in the local inflammatory network will also be investigated.
项目描述(申请人提供):本项目的目的是研究瘦素缺乏调节小鼠肠道炎症易感性的机制。除了作为食物摄入和能量消耗的调节剂外,瘦素还调节免疫和炎症反应。初步数据表明,瘦素缺陷型(ob/ob)和瘦素受体缺陷型(db/db)小鼠对由DSS或TNBS的长期施用诱导的结肠炎具有抗性。本申请将尝试鉴定导致观察到的效应的细胞群。在具体目标1中,评估神经元瘦素受体(Ob-R)在肠道炎症调节中的相对作用。DSS和TNBS将被施用到神经元中Ob-R选择性缺乏的小鼠,并且它们的反应与WF小鼠的反应相比。为了更详细地分析下丘脑Ob-R的作用,将在小鼠中研究DSS和TNBS诱导的肠道炎症,其中通过将表达cre重组酶的载体注射到Ob-Rflox/flox小鼠中,在下丘脑的弓状核和腹内侧核中特异性地缺失Ob-R。由于瘦素对骨髓和非骨髓来源的细胞的作用可能有助于DSS和TNBS给药模型中结肠炎的调节,因此在具体目标2中,将使用Ob-R的骨髓嵌合体研究Ob-R在这两个细胞群中表达的相对贡献。WT骨髓将被移植到db/db小鼠中,而WT小鼠将接受db/db骨髓,并将研究结肠炎的发展。此外,瘦素对T淋巴细胞的直接影响。初步数据表明,在CD 4 + CD 45 RBhigh细胞转移到SCID小鼠的模型中,供体T淋巴细胞上的Ob-R表达调节结肠炎的诱导。转移模型将被用于试图剖析Ob-R表达在供体T淋巴细胞与受体小鼠细胞中所起的相对作用。为了研究T淋巴细胞中Ob-R表达在DSS或TNBS诱导的结肠炎的调节中的直接作用,将使用T淋巴细胞中Ob-R选择性缺失的小鼠。最后,在Specific Aim 3中,将在小鼠模型和IBD患者的活检中评估免疫细胞在肠道炎症部位产生瘦素。还将研究免疫源性瘦素在局部炎症网络中的可能参与。
项目成果
期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Adiponectin deficiency does not affect the inflammatory response to endotoxin or concanavalin a in mice.
脂联素缺乏不影响小鼠对内毒素或刀豆球蛋白 a 的炎症反应。
- DOI:10.1210/en.2006-0855
- 发表时间:2006
- 期刊:
- 影响因子:4.8
- 作者:Pini,Maria;Sennello,JosephA;Chan,Lawrence;Fantuzzi,Giamila
- 通讯作者:Fantuzzi,Giamila
Adipokines in cord blood and risk of wheezing disorders within the first two years of life.
脐带血中的脂肪因子和出生后两年内出现喘息性疾病的风险。
- DOI:10.1111/j.1365-2222.2007.02759.x
- 发表时间:2007
- 期刊:
- 影响因子:0
- 作者:Rothenbacher,D;Weyermann,M;Fantuzzi,G;Brenner,H
- 通讯作者:Brenner,H
Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice.
T 淋巴细胞上的瘦素受体表达可调节小鼠的慢性肠道炎症。
- DOI:10.1136/gut.2003.027136
- 发表时间:2004
- 期刊:
- 影响因子:24.5
- 作者:Siegmund,B;Sennello,JA;Jones-Carson,J;Gamboni-Robertson,F;Lehr,HA;Batra,A;Fedke,I;Zeitz,M;Fantuzzi,G
- 通讯作者:Fantuzzi,G
T cell-mediated hepatic inflammation modulates adiponectin levels in mice: role of tumor necrosis factor alpha.
T 细胞介导的肝脏炎症调节小鼠脂联素水平:肿瘤坏死因子 α 的作用。
- DOI:10.1016/j.metabol.2005.11.008
- 发表时间:2006
- 期刊:
- 影响因子:0
- 作者:Morris,AlisonM;Sennello,JosephA;Fayad,RajaA;Eckel,RobertH;Dinarello,CharlesA;Fantuzzi,Giamila
- 通讯作者:Fantuzzi,Giamila
Effect of adiponectin deficiency on intestinal damage and hematopoietic responses of mice exposed to gamma radiation.
脂联素缺乏对γ辐射小鼠肠道损伤和造血反应的影响。
- DOI:10.1016/j.mrfmmm.2009.06.014
- 发表时间:2010
- 期刊:
- 影响因子:0
- 作者:Ponemone,Venkatesh;Fayad,Raja;Gove,MelissaE;Pini,Maria;Fantuzzi,Giamila
- 通讯作者:Fantuzzi,Giamila
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Giamila Fantuzzi其他文献
Giamila Fantuzzi的其他文献
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{{ truncateString('Giamila Fantuzzi', 18)}}的其他基金
A model of obesity-associated severe acute pancreatitis
肥胖相关重症急性胰腺炎模型
- 批准号:
7229964 - 财政年份:2006
- 资助金额:
$ 29.56万 - 项目类别:
A model of obesity-associated severe acute pancreatitis
肥胖相关重症急性胰腺炎模型
- 批准号:
7033425 - 财政年份:2006
- 资助金额:
$ 29.56万 - 项目类别:
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