Tissue Factor and Emdometriosis
Tissue Factor and Emdometriosis
批准号:
7318129
负责人:
CHARLES JOSEPH LOCKWOOD
金额:
$28.84万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-04-01 至 2012-03-31
关键词:
AccountingActivated Natural Killer CellAdhesionsAgonistAngiogenic FactorApoptosisBindingBlood Coagulation Factor VIICell LineCellsConditioned Culture MediaCoupledDiseaseEndometrialEndometriumEndopeptidasesEndothelial CellsEndotheliumEpithelialEpithelial CellsEtiologyFactor XaFocal AdhesionsGene ExpressionGlandGrowthHemorrhageHumanImmunoconjugatesImmunoglobulin GImmunotherapyImplantIncubatedInfertilityInfiltrationInflammationInflammatoryIntegrinsInterleukin-8InterleukinsMalignant - descriptorMatrix MetalloproteinasesMeasuresMediatingMediator of activation proteinMessenger RNAMetaplasiaModelingMolecularMonocyte Chemoattractant Protein-1MusMutateNatural Killer CellsNumbersOvarianPAR-2 ReceptorPainPathogenesisPathway interactionsPatientsPelvisPeptide HydrolasesProductionProteinsReactive Oxygen SpeciesRecruitment ActivityReportingRetrograde MenstruationReverse Transcriptase Polymerase Chain ReactionRoleSCID MiceSignal TransductionStagingSteroidsStromal CellsTestingThromboplastinTimeTissuesTransplantationTubeUterine cavityVascular Endothelial Growth FactorsWomanangiogenesisbasecell motilitycytokineendometriosisimmortalized celllaser capture microdissectionmacrophagemouse modelnatural Blastocyst Implantationnovelpreventprotein expressionreceptorresponse
中文摘要
子宫内膜异位症是由子宫内膜异位症引起的盆腔粘连,出血,
不孕不育和疼痛。子宫内膜异位植入物的长期存活率与局部显著相关
炎症、强烈的血管生成和组织因子(TF)的过度表达。在许多恶性和恶性疾病中
炎症状态,Tf与V1a因子结合,激活2型蛋白酶激活的受体(PAR-2)上调表达
炎性细胞因子、基质金属蛋白酶与血管的表达
内皮生长因子(VEGF)促进细胞侵袭和血管生成。新的初步结果表格
我们假设子宫内膜异位症组织的侵袭、生长和血管生成是由
子宫内膜细胞和浸润性巨噬细胞的组织因子表达增强。因子VII的后续结合
TO TF激活PAR-2,诱导血管生成、蛋白水解性和炎性介质的表达。这个
后者进而诱导邻近内皮细胞表达PAR-2和血管生成因子受体。
以产生强大的血管生成反应。一种新型的免疫偶联分子(ICON)
突变的第VII因子结构域和免疫球蛋白Fc效应域,靶向Tf,同时也招募激活的Natural
杀伤(NK)细胞。初步结果还表明,ICON抑制了血管的生长和新生
表达转铁蛋白的人子宫内膜上皮细胞株移植到重度联合免疫缺陷
小鼠(SCID)。鉴于过表达的转铁蛋白在子宫内膜异位症的发生和生长中的重要作用
我们假设ICON治疗将根除子宫内膜异位症植入物。为了检验这些假设,我们
目的:1)研究Tf和PAR-2在骨肉瘤中的表达和定位。
子宫内膜异位症患者在位和异位内膜;2)探讨子宫内膜异位症的分子途径(S)
Tf/V11a/PAR-2信号在子宫内膜上皮细胞、间质细胞和巨噬细胞中的表达及其作用
这类信号在内皮细胞迁移、增殖、管状形成和凋亡中的作用;以及3)
在小鼠模型中确定ICON治疗是否能根除子宫内膜异位植入物。这些研究
检查原始致病模型以解释子宫内膜异位植入物的存活和增殖
评估一种新的、无毒的治疗方法,可以根除子宫内膜异位症植入物。
英文摘要
Endometriosis results from extrauterine endometrial implants that cause pelvic adhesions, bleeding,
infertility, and pain. Long-term survival of endometriotic implants is associated with marked local
inflammation, vigorous angiogenesis and over-expression of tissue factor (TF). In a number of malignant and
inflammatory states, TF bound to factor Vila, activates the type-2 protease activated receptor (PAR-2) to upregulate
the expression of inflammatory cytokines, matrix metalloproteinases (MMP) and vascular
endothelial growth factor (VEGF) to promote cell invasion and angiogenesis. Novel Preliminary Results form
the basis of our hypothesis that nidation, growth and angiogenesis of endometriotic tissue results from
enhanced TF expression in endometrial cells and infiltrating macrophages. Subsequent binding of factor VII
to TF activates PAR-2 to induce expression of angiogenic, proteolytic and inflammatory mediators. The
latter, in turn, induce expression of PAR-2 as well as angiogenic factor receptors in adjacent endothelial cells
to generate a potent angiogenic response. A novel immunoconjugate molecule (ICON) comprised of two
mutated factor VII domains and an IgG Fc effector domain, targets TF while also recruiting activated Natural
Killer (NK) cells. Preliminary Results also demonstrate that ICON blocks the growth and angiogenesis in a
TF-expressing human endometrial epithelial cell line transplanted into severe combined immunodeficient
mice (SCID). Given the integral importance of over-expressed TF in the nidation and growth of endometriotic
implants, we posit that ICON treatment will eradicate endometriotic implants. To test these hypotheses we
propose the following Specific Aims: 1) To characterize the expression and localization of TF and PAR-2 in
eutopic and ectopic endometrium from endometriosis patients; 2) To assess the molecular pathway(s) of
TF/Vlla/PAR-2 signaling in endometrial epithelial and stromal cells, and macrophages as well as the effects
of such signaling on endothelial cell migration, proliferation, tube formation and apoptosis; and 3) to
determine if treatment with ICON eradicates endometriotic implants in a murine model. These studies
examine an original pathogenic model to account for the survival and proliferation of endometriotic implants
and evaluate a novel, non-toxic therapy that could eradicate endometriotic implants.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:7714226
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项目类别:
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资助金额:$20.61万
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财政年份:2009
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负责人:CHARLES JOSEPH LOCKWOOD
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批准号:6971576
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批准号:7795475
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负责人:CHARLES JOSEPH LOCKWOOD
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依托单位:
The Yale WRHR Career Development Center
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批准号:6891445
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项目类别:
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资助金额:$40.0万
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财政年份:2004
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负责人:CHARLES JOSEPH LOCKWOOD
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依托单位:
The Yale WRHR Career Development Center
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批准号:6786470
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项目类别:
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资助金额:$40.0万
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财政年份:2004
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负责人:CHARLES JOSEPH LOCKWOOD
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依托单位:
The Yale WRHR Career Development Center
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批准号:7061631
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项目类别:
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资助金额:$40.0万
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财政年份:2004
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负责人:CHARLES JOSEPH LOCKWOOD
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依托单位:
The Yale WRHR Career Development Center
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批准号:7285549
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项目类别:
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资助金额:$40.0万
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财政年份:2004
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负责人:CHARLES JOSEPH LOCKWOOD
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依托单位:
The Yale WRHR Career Development Center
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批准号:7942000
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项目类别:
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资助金额:$47.52万
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财政年份:2004
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负责人:CHARLES JOSEPH LOCKWOOD
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依托单位:
The Yale WRHR Career Development Center
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批准号:7489271
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项目类别:
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资助金额:$40.0万
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财政年份:2004
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负责人:CHARLES JOSEPH LOCKWOOD
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依托单位:
Decidual-Endothelial Tissue Factor and IUGR
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批准号:6774800
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项目类别:
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资助金额:$61.73万
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财政年份:2003
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负责人:CHARLES JOSEPH LOCKWOOD
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依托单位:
Decidual-Endothelial Tissue Factor and IUGR
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批准号:6580084
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项目类别:
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资助金额:$61.99万
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负责人:CHARLES JOSEPH LOCKWOOD
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依托单位:
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依托单位:
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资助金额:$3.79万
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依托单位:
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依托单位:
SGI Meeting: Training and Development Plan
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依托单位:
PREDICTION OF PRETERM DELIVERY USING CERVICAL SONOGRAPHY, FETAL FIBRONECTIN, IL 6
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批准号:6305937
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项目类别:
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资助金额:$2.1万
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依托单位:
PROGESTIN EFFECTS ON UTERINE HOMEOSTASIS AND ANGIOGENESIS
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依托单位: