Genetically Altered Mesenchymal Stem Cell; Paracrine Effect on Neovascularization
基因改变的间充质干细胞;
基本信息
- 批准号:7599600
- 负责人:
- 金额:$ 39万
- 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:2003-04-01 至 2013-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAngiogenic FactorAnimalsAttenuatedBackBiological AssayBlood VesselsBlood capillariesBlood flowBone MarrowBone Marrow CellsBone Marrow Stem CellBone Marrow TransplantationCadherinsCaliberCardiacCellsCollecting CellConditioned Culture MediaCoronary OcclusionsCoronary VesselsCorrosion CastingDataDevelopmentDiseaseEndothelial CellsFibroblast Growth FactorGanciclovirGelGene DeliveryGenesGrantHeartHeart failureHome environmentHypoxiaImageImmunologicsIn VitroInfarctionInjection of therapeutic agentInjuryLaboratoriesLacZ GenesLectinMarrowMeasuresMediatingMediator of activation proteinMesenchymal Stem Cell TransplantationMesenchymal Stem CellsMessenger RNAModelingMolecularMolecular ProfilingMusMyocardialMyocardial InfarctionMyocardial IschemiaMyocardiumPathway interactionsPhosphatidylinositide 3-Kinase InhibitorPlayProcessProductionProteinsRelative (related person)ReporterRodentRoleSignal TransductionSimplexvirusSmall Interfering RNAStaining methodStainsStem cellsSubfamily lentivirinaeTestingTherapeuticThymidine KinaseTransplantationTubeVascular Endothelial Growth FactorsWild Type Mouseangiogenesisbehavior influencecapillarycell motilitycellular transductioncytokinedensitydesignhypoxia inducible factor 1improvedin vitro Assayin vivoinhibitor/antagonistinjuredkillingsneovascularizationneovasculatureparacrinepromoterprotective effectpublic health relevancerepairedsuicide genetranscription factorvasculogenesis
项目摘要
DESCRIPTION (provided by applicant): We have previously demonstrated that mesenchymal stem cells (MSC), when injected into rodent hearts following myocardial infarction (MI), enhance myocardial repair and restore cardiac function. Moreover, this protective effect is enhanced by transduction of the MSC with the cytoprotective gene Akt (Akt-MSC). Furthermore, our data showed that these cells express paracrine mediators that reduce myocardial injury. In this application we hypothesize that Akt-MSC enhance myocardial repair, in part, through its paracrine effects on angiogenesis. Indeed we have shown in our laboratory that Akt-MSCs express multiple angiogenic cytokines such as VEGF and FGF. Moreover, media collected from these cells induce endothelial cell migration and tube formation in vitro. Importantly, we have recently demonstrated that Akt-MSC induces neovascularization in the infarcted heart. Since it has been shown that angiogenic signals mobilize bone marrow derived endothelial progenitor cells (EPC) that home to the ischemic myocardium, we hypothesize that (i) Akt-MSC increase angiogenesis in the post infarct heart through paracrine mechanisms and contribute to improved myocardial repair and function (ii) Akt-MSC increase angiogenesis in part through the recruitment of bone marrow derived EPCs and (iii) Akt-MSC mediated EPC recruitment is controlled by HIF 11. To test these hypotheses, we will investigate the capability of Akt-MSCs or media collected from these cells to stimulate EPC migration and tube formation in vitro and the ability to enhance neovascularization in the post infarcted heart in vivo. We will also examine the contribution of the potential Akt-MSC derived factors towards these processes. Next we will study the role of bone marrow progenitor cells in Akt-MSC induced neovascularization in ischemic myocardium in irradiated/bone marrow transplantation models using genetically marked donor cells. Moreover we will use a "suicide" gene delivery approache to selectively eliminate the bone marrow progenitor cells which may play a role in Akt-MSC mediated neovascularization. Finally, we will investigate the role of hypoxia and Akt regulated transcription factor HIF11 as a molecular switch which may regulate Akt-MSC induced bone marrow cell recruitment to the ischemic myocardium. These studies should help elucidate the mechanism by which Akt-MSCs provide such dramatic and long term protection of the infarcted myocardium and may identify potential therapeutic approaches. PUBLIC HEALTH RELEVANCE The protective effects of adult bone marrow stem cells in the injured heart have been demonstrated, however, the exact mechanism is unknown. In this study, we will examine the effects of these bone marrow cells in the development of new blood vessels in the infarcted heart. Enhancement of new vessels in the heart will greatly aid in the treatment of coronary vessel disease and heart failure.
描述(申请人提供):我们先前已经证明,当心肌梗死(MI)后将间充质干细胞(MSC)注射到啮齿动物心脏中时,可以增强心肌修复和恢复心功能。此外,通过转导带有细胞保护基因Akt的MSC(Akt-MSC),这种保护作用得到了增强。此外,我们的数据显示,这些细胞表达旁分泌介质,从而减少心肌损伤。在这一应用中,我们假设Akt-MSC增强心肌修复,部分是通过其对血管生成的旁分泌作用。事实上,我们的实验室已经证明,Akt-MSCs表达多种血管生成细胞因子,如血管内皮生长因子和成纤维细胞生长因子。此外,从这些细胞收集的培养液在体外诱导内皮细胞迁移和管状形成。重要的是,我们最近证明了Akt-MSC可以在梗塞的心脏中诱导新生血管。由于已经证明血管生成信号动员了定位于缺血心肌的骨髓来源的内皮祖细胞(EPC),我们假设(I)Akt-MSC通过旁分泌机制增加梗死后心脏的血管生成,并有助于改善心肌修复和功能(Ii)Akt-MSC部分通过募集骨髓来源的EPC增加血管生成,(Iii)Akt-MSC介导的EPC募集受HIF 11控制。为了验证这些假设,我们将研究从这些细胞收集的Akt-MSCs或从这些细胞收集的培养液在体外刺激EPC迁移和管状形成的能力,以及在体内促进梗死后心脏新生血管的能力。我们还将研究潜在的Akt-MSC衍生因子对这些过程的贡献。接下来,我们将使用基因标记的供体细胞在辐射/骨髓移植模型中研究骨髓前体细胞在Akt-MSC诱导的缺血心肌新生血管中的作用。此外,我们将使用“自杀”基因传递方法选择性地清除可能在Akt-MSC介导的新生血管中发挥作用的骨髓前体细胞。最后,我们将探讨缺氧和Akt调节的转录因子HIF11在调节Akt-MSC诱导的骨髓细胞向缺血心肌募集的分子开关中的作用。这些研究应该有助于阐明Akt-MSCs对梗塞心肌提供如此戏剧性和长期保护的机制,并可能确定潜在的治疗方法。公共卫生相关性成人骨髓干细胞对受损心脏的保护作用已被证明,然而,确切的机制尚不清楚。在这项研究中,我们将研究这些骨髓细胞在梗死心脏新血管发育中的作用。心脏新血管的增强将极大地帮助治疗冠状动脉疾病和心力衰竭。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Victor J Dzau其他文献
Strategic imperatives for health in the USA: a roadmap for the incoming presidential administration
美国健康领域的战略要务:新总统政府的路线图
- DOI:
10.1016/s0140-6736(24)02189-5 - 发表时间:
2024-12-07 - 期刊:
- 影响因子:88.500
- 作者:
Victor J Dzau;Melissa H Laitner;Emily L Shambaugh - 通讯作者:
Emily L Shambaugh
276 ANDROGEN REGULATES SUBMANDIBULAR GLAND (SMG) RENIN SYNTHESIS AND SECRETICN AT MULTIPLE SITES
- DOI:
10.1203/00006450-198504000-00306 - 发表时间:
1985-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Julie R Ingelfinger;Richard E Pratt;Timothy P Roth;Victor J Dzau - 通讯作者:
Victor J Dzau
Health-care workforce implications of the emDobbs v Jackson Women's Health Organization/em decision
emDobbs 诉杰克逊妇女健康组织案裁决对医疗保健劳动力的影响
- DOI:
10.1016/s0140-6736(24)00581-6 - 发表时间:
2024-06-22 - 期刊:
- 影响因子:88.500
- 作者:
Claire D Brindis;Melissa H Laitner;Ellen Wright Clayton;Susan C Scrimshaw;Barbara J Grosz;Lisa A Simpson;Sara Rosenbaum;Corale L Brierley;Melissa A Simon;Yvette Roubideaux;Bruce N Calonge;Paula A Johnson;Laura DeStefano;Ashley Bear;Kavita S Arora;Victor J Dzau - 通讯作者:
Victor J Dzau
Societal implications of the emDobbs v Jackson Women's Health Organization/em decision
多布斯诉杰克逊妇女健康组织案判决的社会影响
- DOI:
10.1016/s0140-6736(24)00534-8 - 发表时间:
2024-06-22 - 期刊:
- 影响因子:88.500
- 作者:
Claire D Brindis;Melissa H Laitner;Ellen Wright Clayton;Susan C Scrimshaw;Barbara J Grosz;Lisa A Simpson;Sara Rosenbaum;Corale L Brierley;Melissa A Simon;Yvette Roubideaux;Bruce N Calonge;Paula A Johnson;Laura DeStefano;Ashley Bear;Kavita S Arora;Victor J Dzau - 通讯作者:
Victor J Dzau
406-1 Hypoxia regulatable Aav-2 vector protects against cardiac ischemia/reperfusion injury
- DOI:
10.1016/s0735-1097(04)92260-7 - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Alok S Pachori;Luis G Melo;Lunan Zhang;Richard E Pratt;Victor J Dzau - 通讯作者:
Victor J Dzau
Victor J Dzau的其他文献
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{{ truncateString('Victor J Dzau', 18)}}的其他基金
Novel strategy for Enhancing miRNA as a Therapeutic for Cardiac Regeneration
增强 miRNA 作为心脏再生治疗的新策略
- 批准号:
9237608 - 财政年份:2016
- 资助金额:
$ 39万 - 项目类别:
Sfrp2 and Cardiac Progenitor Cells in Regenerative Response to Ischemic Injury
Sfrp2 和心脏祖细胞对缺血性损伤的再生反应
- 批准号:
8239268 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
Sfrp2 as a Stem Cell Derived Paracrine Factor for Cardioprotection
Sfrp2 作为干细胞衍生的旁分泌因子,具有心脏保护作用
- 批准号:
7145291 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
Sfrp2 and Cardiac Progenitor Cells in Regenerative Response to Ischemic Injury
Sfrp2 和心脏祖细胞对缺血性损伤的再生反应
- 批准号:
8590214 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
Sfrp2 as a Stem Cell Derived Paracrine Factor for Cardioprotection
Sfrp2 作为干细胞衍生的旁分泌因子,具有心脏保护作用
- 批准号:
7642490 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
Sfrp2 and Cardiac Progenitor Cells in Regenerative Response to Ischemic Injury
Sfrp2 和心脏祖细胞对缺血性损伤的再生反应
- 批准号:
8786586 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
Sfrp2 as a Stem Cell Derived Paracrine Factor for Cardioprotection
Sfrp2 作为干细胞衍生的旁分泌因子,具有心脏保护作用
- 批准号:
7446063 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
Sfrp2 and Cardiac Progenitor Cells in Regenerative Response to Ischemic Injury
Sfrp2 和心脏祖细胞对缺血性损伤的再生反应
- 批准号:
8403716 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
Sfrp2 as a Stem Cell Derived Paracrine Factor for Cardioprotection
Sfrp2 作为干细胞衍生的旁分泌因子,具有心脏保护作用
- 批准号:
7286054 - 财政年份:2006
- 资助金额:
$ 39万 - 项目类别:
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