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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。的显著损失心肌梗死（MI）引起的心肌细胞损伤可导致心脏功能的进行性恶化。尽管有最佳的药物治疗，许多患者的心脏功能仍无法恢复，不利的结构和电重构导致具有致命后果的心力衰竭（HF）。HF残留一种致命的临床综合征，5年死亡率为45- 60%。因此，迫切需要寻求新的终末期HF患者的选择。由于成年心肌细胞不能充分增殖，损伤组织，干细胞疗法代表了治疗终末期HF的新的有希望的方法，因为其目的是产生新的功能性心肌和诱导新血管生成。然而，主要的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。环境。我们最近发表了令人信服的数据，以证明移植的主要原因之一，干细胞损失是鼠MI后模型中的炎症。因此，本提案的总体目标是靶基因参与炎症途径的体细胞，将被移植，以改善终末期HF的移植结局。该提案提出了炎症诱导细胞的关键作用，严重阻碍心脏干细胞治疗的死亡。成功完成将为促进未来终末期HF患者的个性化心血管护理和移植治疗的转化从实验室到临床实践。