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Cardiac Revascularization with Direct Reprogramming Approaches

通过直接重编程方法进行心脏血运重建

基本信息

批准号：
10557918
负责人：
Young-Sup Yoon
金额：
$ 44.91万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-12 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557918
关键词：
Adenovirus Vector Adult American Animals Area Biocompatible Materials Biological Biomedical Engineering Blood Vessels Bone Marrow Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Lineage Cell Reprogramming Cell Survival Cell Therapy Cell Transplantation Cells Clinical Coronary Arteriosclerosis Disease Disease model Echocardiography Embryo Encapsulated Endothelial Cells Endothelium Engineering Ethics Family Fibroblasts Functional disorder Gel Generations Genes Genomics Goals Growth Heart Hepatocyte Histologic Human Impairment Injections Insertion Mutation Ischemia Lentivirus Vector Magnetic Resonance Imaging Medical Modeling Molecular Morbidity - disease rate Mus Myocardial Ischemia Neurons Nitric Oxide Operative Surgical Procedures Patients Peptides Play Population Research Risk Rodent Role Somatic Cell Technology Therapeutic Therapeutic Effect Time Tissue Engineering Tissues Variant Vascularization blood vessel development cardiac regeneration cell type clinical application clinical development clinical translation cost delivery vehicle design heart function improved in vivo induced pluripotent stem cell member microCT mortality nano neovascularization next generation novel novel strategies overexpression peptide amphiphiles postnatal human programs regenerative therapy side effect success transcription factor tumor vector

项目摘要

Project Summary Ischemic heart diseases are the leading cause of morbidity and mortality. The underlying problems of these diseases are loss or dysfunction of blood vessels and insufficient new vessel formation. While cell therapy has emerged as a promising option to promote blood vessel growth, no therapy is yet clinically available and there is much room for improvement. The potential of bone marrow (BM)-derived cells turned out to be minimal9, and embryonic or induced pluripotent stem cell (ESC/iPSC)-derived ECs are difficult to maintain, costly to produce, and may cause side effects. To avoid these problems, a new approach, called direct reprogramming or direct conversion has been developed, in which somatic cells are converted into other lineage cells by overexpression of lineage- or cell-type specific transcription factors (TFs). This approach allows simpler and safer target cell generation and has the potential for more convenient clinical translation. We have attempted this direct reprogramming toward ECs using combinations of seven endothelial-related TFs and demonstrated for the first time that ETV2 alone is sufficient to convert human fibroblasts into ECs. However, since we used a lentiviral vector like others, these rECs have restrictions in clinical applicability. The direct EC reprogramming approach for therapy has two options: cell therapy or direct in vivo reprogramming. For clinical application, both require a safer delivery vector to minimize the possibility of genomic integration. Thus, we developed an adenoviral-ETV2 (Ad-ETV2) vector. Another important obstacle for cell therapy is short- term survival of the transplanted cells. To overcome this problem, we have investigated the potential of biomaterial for prolongation of the cell survival and therapeutic effects. We recently showed that peptide amphiphile (PA) nanomatrix gel is very effective, extending survival of human iPSC-derived ECs longer than 10 months and inducing continuous vessel formation in vivo. In this study, first, we will first develop cell-based therapy. We will generate clinically compatible rECs from human fibroblasts and generate an optimal PA construct combining these rECs with various types of PA nanomatrix gel including a newly developed nitric oxide (NO)-releasing PA. We will then determine the vascularization and therapeutic effects of the selected rEC-PA nanomatrix constructs on rodent ischemic heart disease models. Second, we will investigate whether direct delivery of Ad-ETV2 into cardiac ischemia models can directly reprogram fibroblasts into functional endothelial cells and induce vascularization in vivo. We will use genetically modified mice to track the fate of fibroblasts toward ECs in vivo. The goal of this project is to develop clinically applicable cardiac revascularization strategy using a novel direct reprogramming approach combined with tissue engineering technologies. If successful, this study will provide next-generation platforms for broad areas of research and therapy for ischemic heart diseases.

项目总结

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

FLT4 as a marker for predicting prognostic risk of refractory acute myeloid leukemia.

DOI：
10.3324/haematol.2022.282472
发表时间：
2023-11-01
期刊：
HAEMATOLOGICA
影响因子：
10.1
作者：
Lee, Ji Yoon;Lee, Sung-Eun;Han, A-Reum;Lee, Jongeun;Yoon, Young-sup;Kim, Hee-Je
通讯作者：
Kim, Hee-Je