Investigating Mitogenic Mechanism and Therapeutic Efficacy of Adenosine Deaminase Knockout in Human and Murine Cardiomyocytes
研究人和小鼠心肌细胞中腺苷脱氨酶敲除的有丝分裂机制和治疗效果
基本信息
- 批准号:10815529
- 负责人:
- 金额:$ 4.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-30 至 2024-09-29
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Abstract
Mammalian cardiomyocytes (CMs) in embryonic and neonatal hearts are proliferative, which allows for heart
regeneration to occur. This proliferative capacity of CMs is lost shortly after birth and in the adult hearts CMs
are largely post-mitotic, renewing at very low rates of less than 1% per year. The inability of adult CMs to
proliferate, along with the absence of resident stem cells capable of robust generation of new CMs, limit the
ability of adult mammalian hearts to self-repair following injury such as myocardial infarction (MI). Preliminary
results from my CRISPR knockout screen in cultured neonatal rat CMs show that knockout of the gene
adenosine deaminase (ADA-KO) results in robust cell cycle activation in both primary rodent and pluripotent
stem cell-derived human CMs in vitro. Follow-up RNA sequencing analysis suggests that ADA-KO alters CM
metabolism. As metabolic alterations have been shown to underlie the pro-proliferative actions of other known
cardiac mitogens, my proposed studies will determine the metabolic and molecular signaling mechanisms
governing ADA-KO mediated proliferation in human CMs. Additionally, I will test the in vitro effects of ADA-KO
on injured engineered cardiac tissues (ECTs) made using polyploid human CMs, which we have shown to be
resistant to division similarly to polyploid CMs in vivo. Furthermore, in proof-of-concept in vivo studies, I will
test therapeutic efficacy of ADA-KO in the setting of myocardial infarction by AAV delivery of ADA-KO sgRNAs
to transgenic mice with CM-specific Cas9 expression, followed by studies of cardiac proliferation and function.
When completed, these cross-species in vitro and in vivo studies will provide better understanding of the roles
of ADA in cardiac metabolism and regeneration and will create a basis for the development of novel gene
therapies for cardiac regeneration.
抽象的
胚胎和新生儿心脏中的哺乳动物心肌细胞(CMS)是增生的,可以使人心脏
再生发生。 CMS的这种增殖能力在出生后不久和成人心脏CMS丢失
在很大程度上是有丝分裂后的,每年的更新率低于1%。成人CMS无法
扩散,以及没有能力生成新CMS的常驻干细胞,限制
成年哺乳动物心脏在受伤后自我修复的能力,例如心肌梗塞(MI)。初步的
我在培养的新生大鼠CMS中CRISPR敲除屏幕的结果表明该基因的敲除
腺苷脱氨酶(ADA-KO)导致一级啮齿动物和多能的稳健细胞周期激活
干细胞衍生的人CMS体外。后续RNA测序分析表明ADA-KO改变了CM
代谢。由于已显示代谢改变是其他已知的促销行为的基础
我提出的研究将确定代谢和分子信号传导机制
管理ADA-KO介导的人类CMS的增殖。此外,我将测试ADA-KO的体外效应
在使用多倍体人CMS制造的受伤的工程心脏组织(ECT)上,我们已证明是
在体内类似于多倍体CMS的抗性。此外,在体内研究概念验证方面,我将
ADA-KO在心肌梗塞中测试治疗功效,通过AAV递送ADA-KO SGRNA
至具有CM特异性CAS9表达的转基因小鼠,然后研究心脏增殖和功能。
完成后,这些在体外和体内研究中的跨物种将提供更好地了解角色
心脏代谢和再生中的ADA,并将为开发新基因创造基础
心脏再生的疗法。
项目成果
期刊论文数量(0)
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数据更新时间:2024-06-01
Sophia Bunnell DeL...的其他基金
Investigating Mitogenic Mechanism and Therapeutic Efficacy of Adenosine Deaminase Knockout in Human and Murine Cardiomyocytes
研究人和小鼠心肌细胞中腺苷脱氨酶敲除的有丝分裂机制和治疗效果
- 批准号:1053637010536370
- 财政年份:2022
- 资助金额:$ 4.25万$ 4.25万
- 项目类别:
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Investigating Mitogenic Mechanism and Therapeutic Efficacy of Adenosine Deaminase Knockout in Human and Murine Cardiomyocytes
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