Epigenic Regulation of Lung Progenitor Repair and Regeneration

描述（由申请人提供）：为了实现肺再生医学的承诺，有必要鉴定和表征影响出生后肺上皮修复的细胞谱系，并有效控制它们的维持、扩增和分化， 成熟和功能性上皮细胞。哮喘和COPD是影响肺的细支气管气道的慢性肺部疾病，并且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，从而导致呼吸功能丧失。我们假设细支气管气道内的上皮祖细胞和调节其扩张和分化的途径对于发生在肺部疾病如哮喘和COPD中的慢性和急性肺损伤后的适当气道修复和再生至关重要。鉴于哮喘和COPD造成的巨大临床负担，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，关注可以使用小分子或“可药物化”方法调节的途径将有利于将基础研究结果直接转化为人类治疗。我们建议利用肺发育、干细胞生物学和肺医学领域领先专家数十年的经验，共同利用新技术扩增和分化内源性肺祖细胞以及诱导多能干细胞（iPSC）。通过关注研究者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iPSC的新技术，肺修复和再生联盟（PennLRRC）的Penn组件将极大地推动该领域朝着产生临床相关疗法以促进肺修复和再生的最终目标发展。PennLRRC Consortium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复杂理解对于优化体内操作或产生离体肺祖细胞及其衍生物至关重要 临床使用。相关性（参见说明）：我们将探索miRNA和HSPs通路在肺再生和发育中的作用，以及在用于肺再生疗法的iPSC的产生和分化中的作用。由于存在miRNA和HSP 70通路的小分子调节剂，我们相信，研究这些通路如何调节肺再生将对肺部疾病新疗法的开发产生重要影响

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