Epigenic Regulation of Lung Progenitor Repair and Regeneration

描述(申请人提供)：为了实现再生医学在肺中的前景，有必要鉴定和表征影响出生后肺上皮修复的细胞系，并有效地控制它们的维持、扩增和分化为 成熟的、有功能的上皮细胞。哮喘和慢性阻塞性肺病是慢性肺部疾病，影响肺的细支气管路，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-不适当的再生周期，最终导致正常呼吸道结构和功能的破坏，导致呼吸功能的丧失。我们推测，细支气管内的上皮祖细胞以及调节其扩张和分化的途径对于慢性和急性肺损伤后的适当的呼吸道修复和再生至关重要，这些损伤发生在肺部疾病中，如哮喘和COPD。考虑到哮喘和COPD带来的巨大临床负担，我们相信关注细支气管上皮的修复和再生将对人类健康产生重大而直接的影响。此外，将重点放在可以用小分子或“可用药”方法调节的途径上，将有利于将基础研究成果直接转化为人类疗法。我们建议利用肺发育、干细胞生物学和肺部医学领域的领先专家数十年的经验，合作利用新技术来扩增和分化内源性肺祖细胞以及来自诱导多能干细胞(IPSCs)的祖细胞。通过专注于研究实验室中涉及细支气管上皮祖细胞表观遗传调控的新发现以及产生IPSCs的新技术，宾夕法尼亚大学肺修复和再生联盟(PennLRRC)的组成部分将极大地推动该领域的最终目标，即产生促进肺修复和再生的临床相关疗法。PennLRRC协会的基本论点是，对涉及miRNA和HDAC通路的基本表观遗传机制的复杂理解将对在体内最佳地操纵或产生体外肺祖细胞及其衍生物至关重要 供临床使用。相关性(见说明)：我们将探索miRNA和HDAC通路在肺再生和发育中的作用，以及在肺再生治疗中使用的ipSCs的产生和分化。由于miRNA和hdac通路的小分子调节剂的存在，我们相信对这些通路如何调节肺再生的研究将对肺部疾病新疗法的发展产生重要影响。

DESCRIPTION (provided by applicant): To fulfill the promise of regenerative medicine in the lung, it will be necessary to identify and characterize the cell lineages that affect postnatal lun 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 airways 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 airway 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 epigenetic regulation of bronchiolar epithelial progenitors as well as novel techniques for generation of iPSCs, the Penn component of the 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 epigenetic 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 differentiation 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