Epigenic Regulation of Lung Progenitor Repair and Regeneration

为了实现肺再生医学的承诺，有必要识别和表征肺组织中的 影响出生后肺上皮修复并有效控制其维持的细胞谱系， 扩增和分化成成熟和功能性上皮细胞。哮喘和慢性阻塞性肺病是慢性肺 影响肺的细支气管气道的疾病，是发病率和死亡率的主要原因。 这两种疾病都被认为涉及慢性损伤-修复-不当再生循环，导致 正常气道结构和功能的最终破坏导致呼吸功能丧失。我们 假设细支气管气道内上皮祖细胞和调节它们的途径 扩张和分化对于慢性和慢性炎症后的适当的AIN/VAY修复和再生是至关重要的， 急性肺损伤发生在肺部疾病，如哮喘和COPD。鉴于巨大的临床 由于哮喘和COPD造成的负担，我们认为关注细支气管的修复和再生 上皮细胞对人体健康有着重要而直接的影响。此外，重点关注的途径， 可以使用小分子或“可药物化”方法进行调节， 人类治疗的基础研究成果。我们建议利用数十年的经验， 肺发育、干细胞生物学和肺医学方面的专家， 用于扩增和分化内源性肺祖细胞以及来源于 诱导多能干细胞（iPSC）。通过关注研究人员实验室的新发现， 细支气管上皮祖细胞的表观遗传调控以及产生 iPSCs是肺修复和再生联盟（PennLRRC）的宾夕法尼亚组成部分， 推动该领域朝着产生临床相关疗法的最终目标发展， 修复和再生。PennLRRC联盟的基本论点是， 对涉及miRNA和HSP 70通路的基本表观遗传机制的理解将是至关重要的 最佳地在体内操作或产生离体肺祖细胞及其衍生物以供临床使用。 相关性（参见说明）： 我们将探讨miRNA和HSP 70通路在肺再生和发育中的作用， 用于肺再生疗法的iPSC的产生和分化。因为小 存在miRNA和HSP 70通路的分子调节剂，我们相信，对这些调节剂如何作用的研究， 调节肺再生的途径将对新疗法的发展产生重要影响， 肺病

To fulfill the promise of regenerative medicine in the lung, it will be necessary to identify and characterize the cell lineages that affect postnatal lung epithelial repair and to effectively control their maintenance, expansion, and differentiation into mature and functional epithelial cells. Asthma and COPD are chronic lung diseases which affect the bronchiolar ainways of the lung and are leading causes of morbidity and mortality. Both diseases are thought to involve a chronic injury-repair-improper regeneration cycle that leads to the eventual breakdown of normal airway structure and function leading to loss of respiratory function. We hypothesize that epithelial progenitors within the bronchiolar airways and the pathways that regulate their expansion and differentiation are critical for proper ain/vay repair and regeneration after both chronic and acute lung injury that occurs in lung diseases such as asthma and COPD. Given the immense clinical burden imposed by asthma and COPD, we believe a focus on repair and regeneration of bronchiolar epithelium will have a significant and direct impact on human health. Moreover, a focus on pathways that can be modulated using small molecule or "druggable" approaches would be beneficial for directly translating basic research findings to human therapy. We propose to leverage decades of experience by leading experts in lung development, stem cell biology, and pulmonary medicine to collaboratively harness novel technologies for expansion and differentiation of endogenous lung progenitors as well as those derived from induced pluripotent stem cells (iPSCs). By focusing on new findings in the investigators laboratories involving the epigenetie regulation of bronchiolar epithelial progenitors as well as novel techniques for generation of iPSCs, the Penn component ofthe Lung Repair and Regeneration Consortium (PennLRRC) will dramatically advance the field towards the ultimate goal of generating clinically relevant therapies for promoting lung repair and regeneration. The underlying thesis of the PennLRRC Consortium is that a sophisticated understanding of basic epigenetie mechanisms involving miRNA and Hdac pathways will be critical to optimally manipulate in vivo or generate ex vivo lung progenitors and their derivatives for clinical use. RELEVANCE (See instructions): We will explore the roles for miRNA and Hdac pathways in lung regeneration and development as well as in the generation and differentitation of iPSCs for use in regenerative therapies in the lung. Since small molecule modulators of miRNA and Hdac pathways exist, we believe that investigation into how these pathways regulate lung regeneration will have an important impact on the development of new therapies for lung disease