Cardiovascular regeneration and pioneer factors
心血管再生和先锋因素
基本信息
- 批准号:10649338
- 负责人:
- 金额:$ 69.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-20 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAdultAffectAlgorithmsAmericanApplications GrantsBindingBioinformaticsBiological AssayBiologyBiotechnologyBloodBlood VesselsBypassCardiacCardiovascular DiseasesCardiovascular systemCaringCellular biologyChIP-seqChromatinChronicCommunicationCoronary Artery BypassDNADataDevelopmentDiabetes MellitusDiseaseDissectionEmbryoEmbryonic DevelopmentEndotheliumEngineeringFibroblastsFutureGene ExpressionGenesGeneticGenetic EngineeringGenetic ModelsGenetic TranscriptionGoalsHeart InjuriesHematopoieticIn VitroIncidenceInflammatoryInjuryKnockout MiceMachine LearningMapsMediatingMedicalModelingMorbidity - disease rateMorphogenesisMusNatural regenerationNatureNucleosomesObesityPathway interactionsPatientsPeripheral arterial diseasePublicationsPublishingRegulator GenesResearchRoleSMARCA4 geneSMARCA5 geneSocietiesSpecific qualifier valueTAL2 geneTherapeuticTherapeutic InterventionVascular Diseasescardiac regenerationcardiac repairclinically significantconditional knockoutin vivoinnovationknock-downlimb amputationmortalitymouse modelmutantneovascularizationnovelnovel therapeuticsprogenitorprogramsrecruitresponse to injuryrevascularization surgerysingle-cell RNA sequencingstem cellstranscription factor
项目摘要
Cardiovascular diseases are both common and deadly. For example, peripheral artery disease affects more
than 10M Americans resulting in more than 150,000 limb amputations each year in the U.S. In addition, more
than 300,000 patients have coronary artery bypass grafting (surgical revascularization). Current medical
therapies for vascular disease include limb amputation and vascular bypass grafting--these therapeutic
interventions have significant limitations. These diseases are chronic, debilitating, lethal and they warrant new
and novel therapies. Previous studies have demonstrated the essential role for pioneer factors that modulate
chromatin accessibility and thereby impact the binding of early transcriptional regulators for lineage
specification. We have recently demonstrated that ETV2 is an essential pioneer factor for endothelial, vascular
and blood lineages. We have used global and conditional gene disruption strategies, fate-mapping, gene
editing, single cell RNA-seq, ATAC-seq and ChIP-seq assays to provide supportive data for this application. In
addition, we defined an important ETV2-miR130a-PDGFRa cascade that governs endothelial development.
Furthermore, our recent publications and our preliminary data support the overall hypothesis that
ETV2 is a pioneer factor that regulates the specification of the endothelial lineage. In these proposed
studies, we will use a number of unique genetic models that we have engineered and we take an innovative
strategy to define the mechanisms whereby ETV2 functions as a pioneer factor to regulate cardiovascular
regeneration. To examine our hypotheses, we will address the following specific aims: Specific Aim #1:
Specific Aim #1: To further define the mechanisms whereby ETV2 functions as a pioneer factor during
embryogenesis and reprogramming to the endothelial lineage; Specific Aim #2: To define the role of
chromatin modifying factors and ETV2 during embryogenesis and reprogramming to the endothelial
lineage and Specific Aim #3: To examine the factors that promote ETV2 mediated reprogramming of
the endothelial lineage in vitro and in vivo. These aims will utilize our recently engineered genetic mouse
models, ATAC-seq, MNase-seq, ChIP-seq, inducible mouse model, cardiac injury model in the adult mouse,
novel and bioinformatics algorithms to comprehensively define the mechanisms whereby ETV2 functions as a
pioneer factor and will serve as prelude for therapeutic initiatives to engineer and promote regeneration of the
cardiovascular lineages. Given the tremendous morbidity and mortality of cardiovascular disease in our
society, the potential impact of this proposal is significant.
心血管疾病既常见又致命。例如,外周动脉疾病影响更多
超过1000万美国人导致超过150,000截肢每年在美国此外,更多
超过30万名患者接受了冠状动脉旁路移植术(外科血管重建术)。当前医学
血管疾病的治疗方法包括截肢和血管旁路移植术,这些治疗方法
干预措施有很大的局限性。这些疾病是慢性的、使人衰弱的、致命的,
和新疗法。先前的研究已经证明了调节细胞凋亡的先驱因子的重要作用。
染色质可及性,从而影响谱系的早期转录调节因子的结合
规范.我们最近已经证明ETV 2是内皮、血管内皮细胞和血管内皮细胞的一个重要的先锋因子。
和血统我们已经使用了全局和条件基因中断策略,命运定位,基因
编辑、单细胞RNA-seq、ATAC-seq和ChIP-seq测定,以为该应用提供支持性数据。在
此外,我们定义了一个重要的ETV 2-miR 130 a-PDGFR α级联反应,其控制内皮发育。
此外,我们最近的出版物和我们的初步数据支持总体假设,
ETV 2是调节内皮谱系特化的先驱因子。在这些建议中,
研究,我们将使用一些独特的基因模型,我们已经设计,我们采取了创新的
定义ETV 2作为调节心血管疾病的先驱因子的机制的策略
再生为了检验我们的假设,我们将讨论以下具体目标:具体目标#1:
具体目标#1:进一步定义ETV 2在治疗过程中作为先锋因子发挥作用的机制。
胚胎发生和重编程为内皮细胞谱系;具体目标#2:确定
胚胎发生过程中的染色质修饰因子和ETV 2以及重编程至内皮细胞
谱系和具体目标#3:检查促进ETV 2介导的细胞重编程的因子。
在体外和体内的内皮细胞谱系。这些目标将利用我们最近设计的基因小鼠
模型,ATAC-seq,MNase-seq,ChIP-seq,诱导型小鼠模型,成年小鼠心脏损伤模型,
新的和生物信息学算法,以全面定义ETV 2作为一个功能的机制,
先锋因素,并将作为治疗计划的前奏,以工程师和促进再生的
心血管谱系鉴于我国心血管疾病的发病率和死亡率极高,
社会,这一建议的潜在影响是巨大的。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
SeATAC: a tool for exploring the chromatin landscape and the role of pioneer factors.
- DOI:10.1186/s13059-023-02954-5
- 发表时间:2023-05-22
- 期刊:
- 影响因子:12.3
- 作者:Gong, Wuming;Dsouza, Nikita;Garry, Daniel J.
- 通讯作者:Garry, Daniel J.
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Daniel J. Garry其他文献
Porcine myogenesis in cloned wildtype and MYF5/MYOD/MYF6-null porcine embryo
克隆野生型和 MYF5/MYOD/MYF6 基因敲除猪胚胎中的猪肌发生
- DOI:
10.1038/s42003-025-07648-1 - 发表时间:
2025-02-11 - 期刊:
- 影响因子:5.100
- 作者:
Yong-Ho Choe;Satyabrata Das;Xiao Ma;Hyeonjeong Lee;Jacob R. Sorensen;Daniel B. Hoffman;Chan-Hee Jo;Casey P. Johnson;Nicolette Cassel;Daniel J. Garry;Sarah M. Greising;Mary G. Garry - 通讯作者:
Mary G. Garry
Promoting cardiomyocyte proliferation for myocardial regeneration in large mammals
促进大型哺乳动物心肌细胞增殖以实现心肌再生
- DOI:
10.1016/j.yjmcc.2024.01.005 - 发表时间:
2024-03-01 - 期刊:
- 影响因子:4.700
- 作者:
Thanh Nguyen;Manuel Rosa-Garrido;Hesham Sadek;Daniel J. Garry;Jianyi (Jay) Zhang - 通讯作者:
Jianyi (Jay) Zhang
Benchmarked approaches for cell lineage reconstructions of in vitro dividing cells and in 1 silico models of Caenorhabditis elegans and Mus musculus developmental trees.
体外分裂细胞和秀丽隐杆线虫和小家鼠发育树的 1 计算机模型中细胞谱系重建的基准方法。
- DOI:
- 发表时间:
2021 - 期刊:
- 影响因子:0
- 作者:
W. Gong;Alejandro A. Granados;Jingyuan Hu;Matthew G. Jones;Ofir Raz;Irepan Salvador;Hanrui Zhang;Ke;Il;R. Retkute;Alidivinas Prusokas;Augustinas Prusokas;Alex Khodaverdian;Richard Zhang;Suhas S. P. Rao;Robert Wang;P. Rennert;V. Saipradeep;N. Sivadasan;Aditya Rao;Thomas Joseph;Rajgopal Srinivasan;Jiajie Peng;Lu Han;Xuequn Shang;Daniel J. Garry;Thomas Yu;Verena Chung;M. Mason;Zhandong Liu;Y. Guan;N. Yosef;J. Shendure;M. Telford;E. Shapiro;M. Elowitz;P. Meyer - 通讯作者:
P. Meyer
The Lillehei Heart Institute: Building on the Shoulders of Giants
- DOI:
10.1007/s12265-008-9070-9 - 发表时间:
2008-10-13 - 期刊:
- 影响因子:2.500
- 作者:
Daniel J. Garry - 通讯作者:
Daniel J. Garry
Response to correspondence on “Reproducibility of CRISPR-Cas9 methods for generation of conditional mouse alleles: a multi-center evaluation”
- DOI:
10.1186/s13059-021-02320-3 - 发表时间:
2021-04-07 - 期刊:
- 影响因子:9.400
- 作者:
Channabasavaiah B. Gurumurthy;Aidan R. O’Brien;Rolen M. Quadros;John Adams;Pilar Alcaide;Shinya Ayabe;Johnathan Ballard;Surinder K. Batra;Marie-Claude Beauchamp;Kathleen A. Becker;Guillaume Bernas;David Brough;Francisco Carrillo-Salinas;Wesley Chan;Hanying Chen;Ruby Dawson;Victoria DeMambro;Jinke D’Hont;Katharine Dibb;James D. Eudy;Lin Gan;Jing Gao;Amy Gonzales;Anyonya Guntur;Huiping Guo;Donald W. Harms;Anne Harrington;Kathryn E. Hentges;Neil Humphreys;Shiho Imai;Hideshi Ishii;Mizuho Iwama;Eric Jonasch;Michelle Karolak;Bernard Keavney;Nay-Chi Khin;Masamitsu Konno;Yuko Kotani;Yayoi Kunihiro;Imayavaramban Lakshmanan;Catherine Larochelle;Catherine B. Lawrence;Lin Li;Volkhard Lindner;Xian-De Liu;Gloria Lopez-Castejon;Andrew Loudon;Jenna Lowe;Loydie Jerome-Majeweska;Taiji Matsusaka;Hiromi Miura;Yoshiki Miyasaka;Benjamin Morpurgo;Katherine Motyl;Yo-ichi Nabeshima;Koji Nakade;Toshiaki Nakashiba;Kenichi Nakashima;Yuichi Obata;Sanae Ogiwara;Mariette Ouellet;Leif Oxburgh;Sandra Piltz;Ilka Pinz;Moorthy P. Ponnusamy;David Ray;Ronald J. Redder;Clifford J. Rosen;Nikki Ross;Mark T. Ruhe;Larisa Ryzhova;Ane M. Salvador;Sabrina Shameen Alam;Radislav Sedlacek;Karan Sharma;Chad Smith;Katrien Staes;Lora Starrs;Fumihiro Sugiyama;Satoru Takahashi;Tomohiro Tanaka;Andrew Trafford;Yoshihiro Uno;Leen Vanhoutte;Frederique Vanrockeghem;Brandon J. Willis;Christian S. Wright;Yuko Yamauchi;Xin Yi;Kazuto Yoshimi;Xuesong Zhang;Yu Zhang;Masato Ohtsuka;Satyabrata Das;Daniel J. Garry;Tino Hochepied;Paul Thomas;Jan Parker-Thornburg;Antony D. Adamson;Atsushi Yoshiki;Jean-Francois Schmouth;Andrei Golovko;William R. Thompson;K. C. Kent Lloyd;Joshua A. Wood;Mitra Cowan;Tomoji Mashimo;Seiya Mizuno;Hao Zhu;Petr Kasparek;Lucy Liaw;Joseph M. Miano;Gaetan Burgio - 通讯作者:
Gaetan Burgio
Daniel J. Garry的其他文献
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{{ truncateString('Daniel J. Garry', 18)}}的其他基金
Project 2 - Shh and Etv2 Signaling Pathways and Cardiovascular Repair in Mouse and Pig
项目 2 - Shh 和 Etv2 信号通路以及小鼠和猪的心血管修复
- 批准号:
10493839 - 财政年份:2022
- 资助金额:
$ 69.74万 - 项目类别:
Project 2 - Shh and Etv2 Signaling Pathways and Cardiovascular Repair in Mouse and Pig
项目 2 - Shh 和 Etv2 信号通路以及小鼠和猪的心血管修复
- 批准号:
10677734 - 财政年份:2022
- 资助金额:
$ 69.74万 - 项目类别:
Bioengineering Strategies for Cardiovascular Disease
心血管疾病的生物工程策略
- 批准号:
10227924 - 财政年份:2019
- 资助金额:
$ 69.74万 - 项目类别:
Bioengineering Strategies for Cardiovascular Disease
心血管疾病的生物工程策略
- 批准号:
10468711 - 财政年份:2019
- 资助金额:
$ 69.74万 - 项目类别:
Regulatory Mechanisms of Endothelial Development and Regeneration
内皮发育和再生的调节机制
- 批准号:
9002076 - 财政年份:2014
- 资助金额:
$ 69.74万 - 项目类别:
Regulatory Mechanisms of Endothelial Development and Regeneration
内皮发育和再生的调节机制
- 批准号:
8668377 - 财政年份:2014
- 资助金额:
$ 69.74万 - 项目类别:
Regulatory Mechanisms of Endothelial Development and Regeneration
内皮发育和再生的调节机制
- 批准号:
8827844 - 财政年份:2014
- 资助金额:
$ 69.74万 - 项目类别:
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