Cardiac Regenerative Therapy Using Gene-Edited Stem Cells to Improve Transplantation Outcomes

使用基因编辑干细胞改善移植结果的心脏再生疗法

基本信息

批准号：
10905166
负责人：
Padmini Sirish
金额：
$ 40.04万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10905166
关键词：
Address Adenosine Triphosphate Adult Atherosclerosis CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Caring Cell Death Cell Death Induction Cell Transplantation Cells Clinical Complex Data Deterioration Electrophysiology (science)Engraftment Environment Experimental Designs Female Fibroblasts Flow Cytometry Future Genes Goals Heart failure Human Inflammasome Inflammation Inflammatory Ischemia Knowledge Leucine-Rich Repeat Ligands Link Mediating Medical Modeling Modification Molecular Molecular Biology Morbidity - disease rate Multiprotein Complexes Mus Myocardial Infarction Myocardium Necrosis Outcome Outcome Study Pathologic Pathway interactions Patient Care Patients Pattern Play Production Proliferating Proteins Publishing Purinoceptor Receptor Gene Recovery of Function Role Sex Differences Side Signal Transduction Somatic Cell Stem cell transplant Stress Syndrome Testing Therapeutic Intervention Tissues Translating Translations Transplantation United States Western Blotting Woman angiogenesis bench to bedside cardiac regeneration cell type clinical practice clinical translation clinically relevant comparison control cytokine exosome extracellular heart function humanized mouse immunocytochemistry improved induced pluripotent stem cell derived cardiomyocytes male marenostrin men mortality new therapeutic target novel therapeutics pharmacologic pre-clinical regenerative therapy response sex stem cell therapy stem cells therapeutic evaluation therapeutic target transplantation therapy

项目摘要

Cardiovascular disease is the leading cause of morbidity and mortality in the United States. A significant loss of cardiomyocytes from myocardial infarction (MI) can result in progressive deterioration of cardiac function. Many patients do not recover their cardiac function despite optimal medical therapies and develop progressive adverse structural and electrical remodeling leading to heart failure (HF) with lethal consequences. HF remains a deadly clinical syndrome with 5-year mortality of 45–60%. Therefore, there is a compelling need to seek new options for patients in end-stage HF. Since adult cardiac myocytes are unable to proliferate sufficiently to replace the damaged tissue, stem cell therapy represents a new promising approach for the treatment of end-stage HF, since it aims at generating new functional myocardium and inducing neoangiogenesis. However, one of the main challenges of cardiac stem cell transplantation is the survival and retention of transplanted cells in the hostile milieu. We have recently published compelling data to demonstrate the one of the main causes of transplanted stem cell loss is inflammation in a murine post-MI model. Therefore, the overarching goal of this proposal is to target genes involved in the inflammatory pathway in somatic cells that will be transplanted, to improve transplantation outcomes in end-stage HF. The proposal addresses the critical role of inflammation induced-cell death that severely impede cardiac stem cell therapy. Successful completion will pave way to facilitate future personalized cardiovascular care for patients with end-stage HF and the translation of transplantation therapies from bench side to clinical practice.

心血管疾病是美国发病率和死亡率的主要原因。心肌梗塞 (MI) 引起的心肌细胞损伤可导致心功能进行性恶化。尽管采取了最佳的药物治疗，许多患者的心脏功能仍未恢复，并出现进展不良的结构和电重塑导致心力衰竭（HF），并导致致命的后果。一种致命的临床综合征，5 年死亡率为 45-60%，因此，迫切需要寻找新的治疗方法。由于成人心肌细胞无法充分增殖以替代心力衰竭患者的选择。受损组织，干细胞疗法代表了治疗终末期心力衰竭的一种新的有前途的方法，因为它的目的是产生新的功能性心肌并诱导新血管生成，但这是主要的之一。心脏干细胞移植的挑战是移植细胞在敌对环境中的存活和保留我们最近发布了令人信服的数据来证明移植的主要原因之一。干细胞损失是小鼠心肌梗死后模型中的炎症，因此，该提案的首要目标是参与将被移植的体细胞炎症途径的靶基因，以改善该提案强调了诱导炎症细胞的关键作用。死亡严重阻碍了心脏干细胞治疗的成功完成将为促进未来铺平道路。终末期心力衰竭患者的个性化心血管护理和移植疗法的转化从实验室到临床实践。