The Burmese Python as a Model System for the Study of Metabolism and Organ Regeneration

项目总结 在这个项目中，我们将研究缅甸蟒蛇(BP)，这是一种快速、大规模、可控和 反复的器官生长。多项研究表明，与实验室哺乳动物和人类不同，BPS 自然觅食很少，它们的觅食习惯与快速和大规模的调控有关 反应和器官生长，随后是消化后退化阶段。这种独特的模式可以 提供关于潜在的适应性、有益、精心安排的增长和衰退的宝贵见解 细胞调节程序以及它们与癌症的不受控制的过程和各种不同的 适应不良的肥厚性或萎缩性疾病状态。在拟议的研究中，我们希望发展更深层次的 特别是对肠道适应的机械性理解。通过研究植物的生长阶段 在喂奶后不久，我们可以发现驱动肠道和其他器官的机制 高效、快速地从休眠状态转为全功能状态。对回归阶段的分析将为我们提供 关于这些机制的有价值的信息，这可能会起到“刹车”的作用，阻止增长。此项目构建 基于并扩展了我们对啮齿动物、蟒蛇和人类的初步比较研究，这揭示了 保守的肠道特征和关键的监管网络。物种间的比较研究有 强大的发现共同的、进化保守的机械性目标、过程和途径 对调查结果的重要性提供进一步的信心。这些差异可能代表着以下机会 为了治疗的好处，试图在哺乳动物中重述，例如，转录模式 在速度上是不同的。我们的数据突出了microRNAs(MiRNAs)的作用，它是一种小的非编码 在转录后水平调节基因表达的RNA。他们是优秀的候选人 调节肠道适应过程的可塑性，因为它们是肠道稳态的主要调节者 和许多功能。此外，由于miRNAs可以在循环中分泌，它们非常适合于 作为肠道和远端组织之间的一种交流方式。在第一个具体目标中，我们寻求 定义动态调节的miRNAs的特征，与肠道的生长和退化平行 BPS和MICE。在第二个具体目标中，我们将开发一种高分辨率的肠道细胞图谱 在BP中，与生长-回归周期相关的转录改变。我们提出了一部小说， 汇聚尖端技术的变革性项目，多学科调查团队 以及一个引人入胜的新动物模型系统，它可以改变现有的研究范式，扩大现有的 研究模式，因为它提供了许多科学和实用的优势。它将启用并设置 进一步的机械论研究的基础，虽然它将产生独特的信息、资源和 有价值的数据集。我们预计，鉴于最近的发展(例如， 基因组注释)，其日益受到重视的优点和公众的兴趣。

PROJECT SUMMARY In this project, we will study Burmese pythons (BPs), a natural paradigm of rapid, massive, controlled and recurring organ growth. Several studies have shown that unlike laboratory mammals and humans, the BPs naturally feed infrequently, and their feeding habits are associated with rapid and massive regulatory responses and organ growth, which is followed by a postdigestion regression phase. This unique model can provide valuable insights about the underlying adaptive, beneficial, well-orchestrated growth and regression cellular regulatory programs and how they differ from the uncontrolled processes of cancer and the various maladaptive hypertrophic or atrophic disease states. In the proposed studies, we hope to develop a deeper mechanistic understanding specifically about intestinal adaptation. By studying the growth phase in the immediate post-feeding period, we can discover those mechanisms that drive the gut and the other organs so efficiently and rapidly from dormancy to full function. The analysis of the regression phase will provide us with valuable information about the mechanisms, which may act as a “brake” and halt growth. This project builds upon and expands our preliminary comparative studies of rodents, pythons and humans, which have revealed conserved intestinal signatures and key regulatory networks. Comparative studies between species are powerful and the discovery of common, evolutionary conserved mechanistic targets, processes and pathways provide further confidence on the significance of the findings. The differences may represent opportunities to harness, for therapeutic benefits by trying to recapitulate in mammals, for example, the transcriptomic patterns that are different in BPs. Our data highlight the role of microRNAs (miRNAs), which are small non-coding RNAs that regulate gene expression at the post-transcriptional level. They are excellent candidates for mediating the plasticity of the intestinal adaptive processes, as they are master regulators of gut homeostasis and many functions. In addition, because miRNAs can be secreted in the circulation, they are ideally suited to serve as a mode of communication between the gut and distal tissues. In the first specific aim, we seek to define a signature of dynamically regulated miRNAs that parallels the growth and regression of the intestine in BPs and mice. In the second specific aim, we will develop a high-resolution cellular atlas of the intestinal transcriptomic changes that are associated with the growth-regression cycles in BPs. We propose a novel, transformative project that brings together cutting-edge technologies, a team of multidisciplinary investigators and a fascinating new animal model system, which could shift current research paradigms and expand current research models, because of the numerous scientific and practical advantages it offers. It will enable and set the foundations for further mechanistic studies, while it will generate unique information, resources and valuable datasets. We anticipate that the interest in this model will grow, given the recent developments (e.g., annotation of the genome), its increasingly appreciated advantages and the interest by the lay public.