Bioengineering Strategies for Cardiovascular Disease

心血管疾病的生物工程策略

• 批准号: 10468711
• 负责人: Daniel J. Garry
• 金额: $ 76.94万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468711
• 关键词: Address; Adolescent; Adult; Affect; American; Animal Model; Biomedical Engineering; Blood; Blood Vessels; Bypass; CRISPR/Cas technology; Cardiovascular Diseases; Cells; Chimera organism; Chronic; Chronic Disease; Clinical; Cloning; Complement; Coronary Artery Bypass; Data; Development; Diabetes Mellitus; Disease; Embryo; Emerging Technologies; Endothelium; Engineering; Family suidae; Future Generations; Genes; Genetic Engineering; Genetically Modified Animals; Goals; Hematological Disease; Hematopoietic; Human; In Vitro; Incidence; Inner Cell Mass; Knock-out; Label; Laboratories; Macaca; Medical; Modeling; Molecular; Morbidity - disease rate; Morphology; Mutant Strains Mice; Obesity; Operative Surgical Procedures; Patients; Peripheral arterial disease; Pharmacology; Physiology; Production; Publications; Publishing; Regenerative Medicine; Regenerative research; Research; Resources; Signal Transduction; Societies; Source; Technology; Technology Transfer; Testing; Therapeutic Intervention; Tissues; Transplantation; Vascular Diseases; Vascular Endothelium; base; blastocyst; boar; body system; clinical application; clinically significant; embryo stage 2; immunological status; in vivo; innovation; innovative technologies; limb amputation; mortality; mutant; nonhuman primate; novel; novel therapeutics; porcine model; programs; response; somatic cell nuclear transfer; stem cell population; stem cells; transcription factor; transcriptome

PROJECT SUMMARY Vascular disease is common and deadly for millions of Americans. Current medical therapies for vascular disease are limited and are associated with significant morbidity and mortality. Therefore, vascular diseases warrant new and novel therapies. The long range goal and the clinical significance of this proposal are to use our newly developed ETV2 knockout pigs as hosts ultimately for the production of personalized human vasculature for clinical applications. The goal of this current revised application is to establish a nonhuman primate platform in a pig that would provide the feasibility for engineering humanized vasculature in a gene edited pig. Our laboratory discovered Etv2 as a downstream target of Nkx2-5 and defined that Etv2 mutant mouse embryos were nonviable and lacked endothelial/vascular and hematopoietic lineages. Using CRISPR/Cas9 gene editing technology, we have further established that ETV2 mutant porcine embryos lack vascular and blood lineages. Based on our results, our overall hypothesis is that Etv2 is an essential factor for the master molecular program for vascular lineages during development. In these proposed studies, we will utilize a number of emerging technologies to engineer a paradigm shifting nonhuman primate vasculature in a genetically modified animal surrogate. To examine our hypotheses, we will address the following specific aims: Specific Aim #1: To define the capacity of blastocyst complementation, using GFP labeled porcine blastomeres, to fully rescue the ETV2 null porcine host; Specific Aim #2: To define the capacity of nonhuman primate stem cell populations for porcine blastocyst complementation and Specific Aim #3: To engineer nonhuman primate vasculature in the ETV2 mutant porcine host. In these studies, we will use state-of-the-art gene technologies and macaque GFP-labeled stem cell populations to engineer a nonhuman primate vasculature in a large animal model. This nonhuman primate large animal model will be an important resource for regenerative medicine and will serve as a platform for generating personalized humanized porcine models. This strategy has the capacity to have a profound impact on the development of emerging therapies for chronic vascular diseases and transplantation. Given the tremendous morbidity and mortality of cardiovascular disease in our society, this proposal could have important clinical impact.

项目总结

项目成果

ETV2-null porcine embryos survive to post-implantation following incomplete enucleation.

ETV2 缺失的猪胚胎在不完全摘除后可存活至植入后。

• DOI: 10.1530/rep-19-0382
• 发表时间: 2020
• 期刊: Reproduction (Cambridge, England)
• 作者: Maeng,Geunho;Gong,Wuming;Das,Satyabrata;Yannopoulos,Demetris;Garry,DanielJ;Garry,MaryG
• 通讯作者: Garry,MaryG