Investigating cardiac repair in a new adult mammalian model for regeneration, the spiny mouse, Acomys cahirinus

每年有近80万美国人心脏病发作，导致许多细胞死亡，幸存的心脏组织中产生疤痕组织。心脏的收缩力永远不会恢复，通常会下降到威胁生存的程度。这是因为成年哺乳动物的心脏没有再生或修复能力。然而，我们发现了一种成年哺乳动物，Acomys属的多刺小鼠，它不会像典型的哺乳动物那样通过结疤来应对器官损伤，而是可以完全再生皮肤、骨骼肌和耳朵等组织。在心脏方面，我们已经证明，在诱发性心脏病发作后的4周内，多刺小鼠心脏的收缩力显示出显着的恢复，并且几乎没有纤维组织沉积。在这个项目中，我们将研究多刺小鼠心脏的细胞在心脏病发作后是否可以增殖，心脏的哪些组织对损伤做出反应，以及哪些基因途径被诱导来刺激这种恢复。发现成年多刺小鼠如何从心脏病发作中恢复的机制并将其转化为人类将对我们社会的健康产生戏剧性的影响。这个项目包括新的本科课程，将让学生参与有意义的研究活动。成年多刺小鼠Acomys的几个组织在受伤后可以完全再生，包括皮肤、肌肉和耳朵，而实验室小鼠的反应是纤维化和结疤。我们已经证明，在心肌梗死后，多刺小鼠心脏的心室组织表现出非常少的纤维化，并可以在4周内恢复其收缩能力，而实验室小鼠则不是这样，心室显示出广泛的损伤和纤维化在整个组织中蔓延。这个项目的目的是，首先，在组织学研究中，通过与实验室小鼠的反应相比较，使用纤维化标志物、增殖标志物和细胞死亡标志物来回答这是否真的是心肌细胞增殖所致的心脏再生的问题。我们将特别关注Acomys是否会形成疤痕，然后愈合或根本不会形成疤痕，我们将使用冷冻损伤模型进一步探讨这一问题。其次，我们将进行RNA-SEQ，以查看受损的Acomys心脏与Mus相比的全球基因表达谱，重点是已知的心外膜和心肌细胞信号通路，并使用药物抑制对这些通路进行功能测试。我们还将确定受损的Acomys心脏中存在的miRNA图谱，并开始对选定的候选者进行功能分析。第三，我们将对受损心脏进行单细胞RNA-SEQ分析，以确定潜在的新细胞基因网络，这可能是Acomy反应改善的原因。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Nearly 800,000 Americans have a heart attack each year which results in the death of many cells and the production of scar tissue in the surviving ventricular tissue. The contractile force of the heart is never recovered and typically declines to a point where survival is threatened. The reason for this is because there is no regenerative or repair capacity in the adult mammalian heart. However, we have discovered an adult mammal, the spiny mouse of the genus Acomys, that does not respond to organ damage in the typical mammalian fashion by scarring, but instead can completely regenerate tissues such as the skin, skeletal muscle and the ear. In the heart we have shown that the contractile force of the spiny mouse heart shows a remarkable recovery over a 4-week period following an induced heart attack and that there is very little fibrotic tissue laid down. In this project we will investigate whether the cells of the spiny mouse heart can proliferate after a heart attack, which tissues of the heart respond to damage and what gene pathways are induced to stimulate this recovery. Discovering the mechanisms of how the adult spiny mouse recovers from a heart attack and translating this to humans will have a dramatic effect on the health of our society. This project includes new undergraduate courses that will engage students in meaningful research activities.Several tissues of the adult spiny mouse, Acomys, can completely regenerate after wounding including skin, muscle and the ear in contrast to the lab mouse which responds by fibrosis and scarring. We have shown that after a myocardial infarction the ventricle tissue of the spiny mouse heart shows very little fibrosis and can recover its contractile force over a 4-week period whereas the lab mouse does not and the ventricle shows widespread damage and a spreading of fibrosis throughout the tissue. This project is intended to, firstly, answer the question of whether this is true cardiac regeneration by cardiomyocyte proliferation in histological studies using fibrosis markers, proliferation markers and cell death markers in comparison to the response of the lab mouse. We will be particularly concerned with whether Acomys forms a scar which then resolves or never forms a scar at all which we will further explore using a cryoinjury model. Secondly, we will perform RNA-seq to look at the global gene expression profile of the damaged Acomys heart compared to Mus with a focus on known epicardial and cardiomyocyte signaling pathways and perform functional tests of these pathways using pharmacological inhibition. We will also identify the miRNA profiles which are present in the damaged Acomys heart and begin a functional analysis of selected candidates. Thirdly, we will perform a single cell RNA-seq analysis of the damaged hearts to identify potentially new cellular gene networks which may be responsible for the improved response in Acomys.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.