Microenvironmental control of progenitors in organ dysfunction and repair

描述(由申请人提供)： 心血管疾病(CVD)可以说是有史以来困扰人类的最大的非传染性医疗保健问题，肺部疾病紧随其后。干细胞/祖细胞有望替代心肌梗死(ML)后的心肌细胞或肺损伤后的肺泡细胞，但对于如何最好地分化这些细胞并确保体内功能方面几乎没有达成一致。我们对心脏和肺再生/修复的方法是创新的，并基于坚实的初步发现。事实上，二十多年来，我们一直在这一领域共同努力，并为加入这个联盟做准备。我们致力于探索天然心肌修复过程的机制基础，发现阻碍有效修复的天然障碍，并设计合成小分子和基于miR的药物疗法和策略来克服这些障碍。我们团队的总体目标是将miRs、小分子和天然干细胞/祖细胞的力量结合起来，剖析控制细胞命运的基本机制，并利用这些新发现最终开发疗法。我们提出了三个具体的目标，这将为治疗性RNA和药物开发提供新的起点，同时扩大心脏和肺再生和修复的机制科学。目标是：目标1.确定自然微环境中的细胞命运机制；目标2.开发病理生理应激/损伤如何促进结构和功能修复的机制信号图；目标3.在整个联盟范围内合作开发教育计划，以引导iPS细胞走向所需的命运并增强其在体内的功能。为了实现这些目标，我们在功能上合并了哈佛大学和德克萨斯大学西南分校的两个协同和互动的祖细胞生物学小组，我们已经通过团队科学产生了有希望的初步数据。作为NHLBI前体细胞生物学联盟的成员，我们建议的Hub将为推进心血管和肺再生医学的这一新前沿做出实质性和重要的贡献。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is arguably the greatest non-infectious health care problem ever to afflict mankind and lung disease is not far behind. Stem/progenitor cells hold great promise to replace cardiomyocytes after myocardial infarction (Ml) or alveoli after lung injury, but there is little agreement on how best to differentiate these cells and ensure in vivo functionality. Our approach to cardiac and lung regeneration/repair is innovative and based on solid preliminary findings. Indeed, collectively we have been working in this field and preparing for participation in this Consortium for more than two decades. We are committed to exploring the mechanistic underpinnings of the native myocardial repair process, discovering natural barriers that prevent effective repair, and devising synthetic small molecule and miR-based pharmaco-therapies and strategies to overcome these barriers. The overall goal of our group will be to combine the power of miRs, small molecules and native stem/progenitor cells to dissect fundamental mechanisms controlling cell fate, and to exploit these new discoveries to ultimately develop therapeutics. We propose three specific aims that will provide new starting points for therapeutic RNA and drug development, while expanding the mechanistic science of cardiac and lung regeneration and repair. The aims are: Aim 1. Define cell fate mechanisms in the native microenvironment; Aim 2. Develop a mechanistic signaling map of how pathophysiological stress/injury promotes structural and functional repair; Aim 3. Collaborate Consortium-wide to develop education programs that can steer iPS cells towards desired fates and enhance their function in vivo. To accomplish these aims, we have functionally merged two synergistic and interactive progenitor cell biology groups at Harvard and UT Southwestern, and we have already generated promising preliminary data through team science. As a member of NHLBI Progenitor Cell Biology Consortium, our proposed Hub will make substantial and important contributions to advancing this new frontier of cardiovascular and pulmonary regenerative medicine.