Regulation of angiogenic balance by thrombospondin-1.
血小板反应蛋白-1 调节血管生成平衡。
基本信息
- 批准号:7390374
- 负责人:
- 金额:$ 36.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-09-30 至 2010-03-31
- 项目状态:已结题
- 来源:
- 关键词:A, CalcineurinAffectAngiogenesis Inducing AgentsAngiogenesis InhibitionAngiogenesis InhibitorsAngiogenic FactorAntibodiesApoptosisApoptosis InhibitorBindingBiochemicalBiologicalBiological AssayCASP8 and FADD-like apoptosis regulating proteinCell DeathCell SurvivalCessation of lifeChromatinCyclin ADataE2F1 geneEMSAEndothelial CellsEndotheliumEpithelialEquilibriumEventFibroblast Growth FactorFibroblast Growth Factor 2GenesImmunoprecipitationIn VitroInduction of ApoptosisInterleukin-2Knockout MiceMAPK11 geneMAPK14 geneMYB geneMediator of activation proteinMolecularMolecular TargetNF-ATNorthern BlottingPathologicPathway interactionsPigmentsProto-Oncogene Proteins c-mybRegulationReporterRoleSignal TransductionSmall Interfering RNAStimulusTNFRSF6 geneTestingTherapeutic InterventionThromboplastinThrombospondin 1Tissue ExpansionTumor Necrosis Factor Ligand Superfamily Member 6Vascular Endothelial Growth FactorsWestern Blottingangiogenesisantiangiogenesis therapycancer therapychromatin immunoprecipitationcyclooxygenase 2extracellularimmunocytochemistryin vivoinhibitor/antagonistkinase inhibitorneutralizing antibodynuclear factors of activated T-cellspromoterreceptorresearch studyresponsestress-activated protein kinase 1transcription factortumor
项目摘要
Inducers of angiogenesis promote endothelial cell (EC) survival, and inhibitors cause apoptosis. Inhibitors
target molecules in the inducer-generated pathways in remodeling EC. In the original proposal we showed
that inhibitors Thrombospondin-1 (TSP1) and pigment epithelial-derived factor (PEDF) increase EC CD95
ligand (CD95L), a death mediator. Inducers upregulate death receptor, CD95, which binds CD95L and
triggers apoptosis, thus blocking angiogenesis. This is how EC balance apoptosis and survival by angiogenic
inhibitors/stimuli. We identified another common target of the pro- and anti-angiogenic factors, the nuclear
factor of activated T-cells (NFAT). NFAT also acts as molecular pivot balancing angiogenesis activation and
inhibition. Promoter array analysis identified activity changes of several transcription factors due to TSP1 and
PEDF including NFicB, cMyb and Egr-1. All three form common network with NFAT. We propose to elucidate
signaling and transcriptional events involved in the NFAT cross-regulation by the pro- and anti-angiogenic
factors. We will use two non-related inhibitors, TSP1 and PEDF, and two stimuli, vascular endothelial growth
factor and basic fibroblast growth factor (VEGF and bFGF). We will determine:
The upstreammediatorsof NFAT deactivation by TSP1 and PEDF. We will evaluate the contribution of
JNKkinases, p38 and GSK in vitro by functional assays with kinase inhibitors, immunoprecipitation and
western blotting. We will analyze the effect of inhibitors on the levels and activity of NFAT proximal activator,
Cacineurin A (CnA) and its modulators, Ca++ mobilization and DSCR-1. Mice null for NFATc2 and CnA will
be used to confirm their functional role.
The regulation of NFAT targets by TSP1 and PEDF. We will screen known NFAT targets Bcl-2, cyclins A and
E, c-FLIP, cyclooxygenase-2 (Cox-2), interleukins and tissue factor by Western and Northern blotting.
Confirmed targets will be evaluated by EMSA and ChIP (chromatin immunoprecipitation) with NFATc2
antibodies and assessed in the in vitro angiogenesis assays with si-RNA or neutralizing antibodies.
NFicB role in the TSP1 and PEDF signaling. NFicB activation will be confirmed by immunocytochemistry and
EMSA. Functional importance will be demonstrated using biochemical inhibitor and/or constitutive^ active
IkB (kB*). Role in the FasL regulation will be examined using inhibitor and by ChIP. Knock-out mice will be
used to verify in vivo NFicB contribution.
The involvement of E2F1,Egr-1 and c-Myb in NFAT action and regulation. Changes in Egr-1 andc-Myb
activity due to TSP1 or PEDF will be confirmed by EMSA. Mice null for Egr and c-Myb will be used to
evaluate their biological role in the anti-angiogeniesis by TSP1 or PEDF. The interaction with NFAT will be
studied using EMSA, IP, and ChlP.A growing body of evidence suggests that activated endothelium is
poised for apoptosis induction by inhibitors.
We will thus delineate molecular targets common for the inhibitors and stimuli and identify major transcription
factors involved in their interaction. These studies will yield new targets for therapeutic intervention using
natural inhibitors.
血管生成诱导剂促进内皮细胞(EC)存活,而抑制剂引起细胞凋亡。抑制剂
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)
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OLGA Valery VOLPERT其他文献
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{{ truncateString('OLGA Valery VOLPERT', 18)}}的其他基金
Apigenin restores TSP-1 expression in UVB-irradiated keratinocytes
芹菜素恢复 UVB 照射的角质形成细胞中 TSP-1 的表达
- 批准号:
8633023 - 财政年份:2013
- 资助金额:
$ 36.66万 - 项目类别:
Apigenin restores TSP-1 expression in UVB-irradiated keratinocytes
芹菜素恢复 UVB 照射的角质形成细胞中 TSP-1 的表达
- 批准号:
9012025 - 财政年份:2013
- 资助金额:
$ 36.66万 - 项目类别:
Maximization of anti-angiogenesis by thrombospondin-1
血小板反应蛋白-1 最大限度地抑制血管生成
- 批准号:
6969494 - 财政年份:2005
- 资助金额:
$ 36.66万 - 项目类别:
Maximization of anti-angiogenesis by thrombospondin-1
血小板反应蛋白-1 最大限度地抑制血管生成
- 批准号:
7260287 - 财政年份:2005
- 资助金额:
$ 36.66万 - 项目类别:
Maximization of anti-angiogenesis by thrombospondin-1
血小板反应蛋白-1 最大限度地抑制血管生成
- 批准号:
7471438 - 财政年份:2005
- 资助金额:
$ 36.66万 - 项目类别:
Maximization of anti-angiogenesis by thrombospondin-1
血小板反应蛋白-1 最大限度地抑制血管生成
- 批准号:
7093581 - 财政年份:2005
- 资助金额:
$ 36.66万 - 项目类别:
Regulation of angiogenic balance by thrombospondin-1
血小板反应蛋白-1 调节血管生成平衡
- 批准号:
6364673 - 财政年份:2001
- 资助金额:
$ 36.66万 - 项目类别:
Regulation of angiogenic balance by thrombospondin-1
血小板反应蛋白-1 调节血管生成平衡
- 批准号:
6779791 - 财政年份:2001
- 资助金额:
$ 36.66万 - 项目类别:
Regulation of angiogenic balance by thrombospondin-1
血小板反应蛋白-1 调节血管生成平衡
- 批准号:
6527785 - 财政年份:2001
- 资助金额:
$ 36.66万 - 项目类别:
Regulation of angiogenic balance by thrombospondin-1.
血小板反应蛋白-1 调节血管生成平衡。
- 批准号:
7216270 - 财政年份:2001
- 资助金额:
$ 36.66万 - 项目类别:
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