Project 2 - Shh and Etv2 Signaling Pathways and Cardiovascular Repair in Mouse and Pig
Project 2 - Shh and Etv2 Signaling Pathways and Cardiovascular Repair in Mouse and Pig
批准号:
10677734
负责人:
Daniel J. Garry
金额:
$43.0万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-01 至 2027-08-31
关键词:
AdultAlgorithmsAnimal ModelApplications GrantsBioinformaticsBirthBlood VesselsCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular systemCell ProliferationClinical ResearchCollaborationsComplementDataDevelopmentDissectionEndotheliumEngineeringFamily suidaeFutureGene ExpressionGeneticGenetic EngineeringGenetic ModelsGoalsGrowthHeartHeart DiseasesHeart InjuriesHeart failureIn VitroInjuryIschemiaKnock-outLaboratoriesLower OrganismMessenger RNAMolecularMolecular AnalysisMorbidity - disease rateMusMuscleMyocardial InfarctionNatural regenerationNeonatalNewtsPathway interactionsPatient CarePatientsProliferatingPublicationsPublishingRegenerative capacityRoleSOX4 geneSignal PathwaySocietiesTechniquesTechnologyTestingTherapeuticTissuesVentricularViral Vectorangiogenesiscardiac regenerationcardiac repairclinically significantcongenital heart disorderexperimental studyheart cellinjuredinnovationmortalitymouse modelmyocardial injurynovelnovel therapeuticsoverexpressionporcine modelpostnatalpre-clinicalprogramsrepairedsynergismtool
中文摘要
摘要
心血管疾病是常见且致命的。虽然低等生物有巨大的能力
成年哺乳动物心脏的再生能力和肌肉再生能力有限
心肌梗塞等损伤后受损组织的损伤。最近,我们定义了一种进化的
蝾螈和小鼠中保守的Shh信号通路,促进体外心肌细胞增殖,
心脏修复我们的初步数据支持这样的假设,即Gli 1(Shh的下游效应子)是一个直接的细胞因子。
Sox 4基因表达和Gli 1过表达的上游调节因子促进心肌细胞增殖,
体外此外,我们已经证明Etv 2是内皮细胞谱系的主要调节因子,
是小鼠和猪血管生成所必需的和足够的。重要的是,这些研究的结果提供了一个
为拟议的研究提供平台,这些研究将剖析管理心血管修复的机制,
增殖因此,我们的总体假设是,Shh下游效应子Gli 1/Gli 2,
心肌细胞以Sox 4依赖性方式增殖,Etv 2促进内皮/血管
共同促进心脏再生。在这些拟议的研究中,我们将使用
在我们的实验室(和核心)中可获得的许多新的遗传模型和大型动物模型,
我们开发的生物信息学算法,我们采用创新的方法来剖析Gli 1的作用,
Etv 2和Sox 4是控制心血管修复和增殖的重要因素。审视我们
假设,修订后的项目2提案将解决以下具体目标:具体目标#1:
定义Gli和Etv 2缺陷心脏的生长和再生能力;具体目标#2:
确定Gli 1和Etv 2过表达对心脏修复和再生的影响,
目的#3:确定Sox 4在心肌细胞谱系中的机制作用。这些目标将
与其他项目相辅相成。他们将利用我们最近改造的基因小鼠
模型、诱导型病毒载体、修饰的mRNA-GFP构建体、小鼠和猪模型、分子分析
和生物信息学算法来全面定义Gli 1、Etv 2和Sox 4作为基本因子的作用
通过促进心肌细胞增殖和血管生成来控制心脏修复和再生
受伤后。鉴于我们社会中心血管疾病的发病率和死亡率非常高,
这项建议的潜在影响是巨大的。
英文摘要
ABSTRACT
Cardiovascular disease is common and deadly. While lower organisms have a tremendous capacity for
regeneration, the adult mammalian heart is more limited in its capacity for regeneration and remuscularization
of the damaged tissue following an injury such as a myocardial infarction. Recently, we defined an evolutionary
conserved Shh signaling pathway in newt and mouse that promotes cardiomyocyte proliferation in vitro and
cardiac repair. Our preliminary data support the hypothesis that Gli1 (a downstream effector of Shh) is a direct
upstream regulator of Sox4 gene expression and Gli1 overexpression promotes cardiomyocyte proliferation in
vitro. Furthermore, we have demonstrated that Etv2 is a master regulator of the endothelial lineage and is
necessary and sufficient for angiogenesis in mouse and pig. Importantly, the results of these studies provide a
platform for the proposed studies that will dissect the mechanisms that govern cardiovascular repair and
proliferation. Therefore, our overall hypothesis is that the Shh downstream effectors, Gli1/Gli2, regulate
cardiomyocyte proliferation in a Sox4 dependent manner and Etv2 promotes endothelial/vascular
development to collectively promote cardiac regeneration. In these proposed studies, we will use a
number of novel genetic models and large animal models that are available in our laboratory (and the cores),
bioinformatics algorithms that we developed and we take an innovative approach to dissect the role of Gli1,
Etv2 and Sox4 as important factors that govern cardiovascular repair and proliferation. To examine our
hypotheses, the revised Project 2 proposal will address the following specific aims: Specific Aim #1: To
define the capacity of Gli and Etv2 deficient hearts for growth and regeneration; Specific Aim #2: To
determine the impact of Gli1 and Etv2 overexpression on cardiac repair and regeneration and Specific
Aim #3: To define the mechanistic role of Sox4 in the cardiomyocyte lineage. These aims will
complement and synergize with the other projects. They will utilize our recently engineered genetic mouse
models, inducible viral vectors, modified mRNA-GFP constructs, mouse and pig models, molecular analyses
and bioinformatics algorithms to comprehensively define the role for Gli1, Etv2 and Sox4 as essential factors
that govern cardiac repair and regeneration by promoting cardiomyocyte proliferation and angiogenesis
following injury. Given the tremendous morbidity and mortality of cardiovascular disease in our society, the
potential impact of this proposal is tremendous.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Cardiovascular regeneration and pioneer factors
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批准号:10649338
-
项目类别:
-
资助金额:$69.74万
-
财政年份:2023
-
负责人:Daniel J. Garry
-
依托单位:
Project 2 - Shh and Etv2 Signaling Pathways and Cardiovascular Repair in Mouse and Pig
-
批准号:10493839
-
项目类别:
-
资助金额:$39.8万
-
财政年份:2022
-
负责人:Daniel J. Garry
-
依托单位:
Bioengineering Strategies for Cardiovascular Disease
-
批准号:10227924
-
项目类别:
-
资助金额:$76.94万
-
财政年份:2019
-
负责人:Daniel J. Garry
-
依托单位:
Bioengineering Strategies for Cardiovascular Disease
-
批准号:10468711
-
项目类别:
-
资助金额:$76.94万
-
财政年份:2019
-
负责人:Daniel J. Garry
-
依托单位:
Regulatory Mechanisms of Endothelial Development and Regeneration
-
批准号:9002076
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项目类别:
-
资助金额:$38.0万
-
财政年份:2014
-
负责人:Daniel J. Garry
-
依托单位:
Regulatory Mechanisms of Endothelial Development and Regeneration
-
批准号:8668377
-
项目类别:
-
资助金额:$38.0万
-
财政年份:2014
-
负责人:Daniel J. Garry
-
依托单位:
Regulatory Mechanisms of Endothelial Development and Regeneration
-
批准号:8827844
-
项目类别:
-
资助金额:$37.43万
-
财政年份:2014
-
负责人:Daniel J. Garry
-
依托单位:
Midwestern Progenitor Cell Consortium
-
批准号:8663942
-
项目类别:
-
资助金额:$109.82万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Midwestern Progenitor Cell Consortium
-
批准号:7833748
-
项目类别:
-
资助金额:$113.25万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Midwestern Progenitor Cell Consortium
-
批准号:8494683
-
项目类别:
-
资助金额:$106.68万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Transcriptional Regulation of Myogenic Stem Cells
-
批准号:8450211
-
项目类别:
-
资助金额:$29.99万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Transcriptional Regulation of Myogenic Stem Cells
-
批准号:7783784
-
项目类别:
-
资助金额:$32.89万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Midwestern Progenitor Cell Consortium
-
批准号:7939720
-
项目类别:
-
资助金额:$110.99万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Transcriptional Regulation of Cardiac Morphogenesis
-
批准号:7851358
-
项目类别:
-
资助金额:$48.81万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Transcriptional Regulation of Myogenic Stem Cells
-
批准号:8230787
-
项目类别:
-
资助金额:$31.57万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Midwestern Progenitor Cell Consortium
-
批准号:8127878
-
项目类别:
-
资助金额:$112.06万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Midwestern Progenitor Cell Consortium
-
批准号:8269040
-
项目类别:
-
资助金额:$112.06万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Midwestern Progenitor Cell Consortium
-
批准号:8842686
-
项目类别:
-
资助金额:$110.41万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Transcriptional Regulation of Cardiac Morphogenesis
-
批准号:7646935
-
项目类别:
-
资助金额:$48.37万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
Transcriptional Regulation of Myogenic Stem Cells
-
批准号:8048170
-
项目类别:
-
资助金额:$31.57万
-
财政年份:2009
-
负责人:Daniel J. Garry
-
依托单位:
海外基金