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:
- 金额:$ 40.04万
- 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:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenosine TriphosphateAdultAtherosclerosisCRISPR/Cas technologyCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular systemCaringCell DeathCell Death InductionCell TransplantationCellsClinicalComplexDataDeteriorationElectrophysiology (science)EngraftmentEnvironmentExperimental DesignsFemaleFibroblastsFlow CytometryFutureGenesGoalsHeart failureHumanInflammasomeInflammationInflammatoryIschemiaKnowledgeLeucine-Rich RepeatLigandsLinkMediatingMedicalModelingModificationMolecularMolecular BiologyMorbidity - disease rateMultiprotein ComplexesMusMyocardial InfarctionMyocardiumNecrosisOutcomeOutcome StudyPathologicPathway interactionsPatient CarePatientsPatternPlayProductionProliferatingProteinsPublishingPurinoceptorReceptor GeneRecovery of FunctionRoleSex DifferencesSideSignal TransductionSomatic CellStem cell transplantStressSyndromeTestingTherapeutic InterventionTissuesTranslatingTranslationsTransplantationUnited StatesWestern BlottingWomanangiogenesisbench to bedsidecardiac regenerationcell typeclinical practiceclinical translationclinically relevantcomparison controlcytokineexosomeextracellularheart functionhumanized mouseimmunocytochemistryimprovedinduced pluripotent stem cell derived cardiomyocytesmalemarenostrinmenmortalitynew therapeutic targetnovel therapeuticspharmacologicpre-clinicalregenerative therapyresponsesexstem cell therapystem cellstherapeutic evaluationtherapeutic targettransplantation 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。重大损失
心肌梗死(MI)引起的心肌细胞死亡可导致心功能进行性恶化。
许多患者尽管接受了最好的药物治疗,但心功能仍未恢复,并发展为进展性的
不利的结构和电气重塑导致心力衰竭(HF),并造成致命后果。HF残留物
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
终末期心力衰竭患者的选择。由于成人心肌细胞不能充分增殖以替代
对于受损的组织,干细胞治疗是治疗终末期心力衰竭的一种新的有希望的方法,
因为它的目的是产生新的功能心肌和诱导新的血管生成。然而,其中一个主要的
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
周围的环境。我们最近公布了令人信服的数据,证明了移植的主要原因之一
在小鼠心肌梗死后模型中,干细胞丢失是炎症。因此,这项提案的首要目标是
体细胞中参与炎症途径的靶基因将被移植,以改善
终末期心力衰竭患者的移植结局。该提案阐述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。成功完成将为未来铺平道路
终末期心力衰竭患者的个性化心血管护理及移植治疗的转译
从板凳边到临床实践。
项目成果
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