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

缅甸蟒蛇作为代谢和器官再生研究的模型系统

• 批准号: 10594758
• 负责人: Nima Saeidi
• 金额: $ 9.17万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10594758
• 关键词: Burmese; Python; Model; System; Study

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.

项目概要 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、受控和 多项研究表明，与实验室哺乳动物和人类不同，BP 具有周期性的器官生长。 自然进食频率较低，它们的进食习惯与快速和大规模的监管有关 这种独特的模型可以影响反应和器官生长，然后是消化后回归阶段。 提供关于潜在的适应性、有益的、精心策划的增长和回归的宝贵见解 细胞调节程序以及它们与癌症和各种不受控制的过程有何不同 在拟议的研究中，我们希望开发更深入的肥厚性或萎缩性疾病状态。 通过研究肠道适应的生长阶段，了解具体的机制。 在喂食后不久，我们可以发现那些驱动肠道和其他器官的机制，以便 高效、快速地从休眠状态到完全功能状态的分析将为我们提供信息。 有关机制的有价值的信息，可能会起到“刹车”的作用并阻止该项目的增长。 并扩展了我们对啮齿动物、蟒蛇和人类的初步比较研究，这些研究揭示了 物种间保守的肠道特征和关键调控网络进行了比较研究。 强大的发现共同的、进化保守的机制目标、过程和途径 进一步增强人们对研究结果重要性的信心。这些差异可能代表着机会。 通过尝试在哺乳动物中重现转录组模式来获得治疗效果 我们的数据强调了 microRNA (miRNA) 的作用，它们是小型非编码物质。 在转录后水平调节基因表达的 RNA 是绝佳的候选者。 介导肠道适应性过程的可塑性，因为它们是肠道稳态的主要调节者 此外，由于 miRNA 可以在循环中分泌，因此它们非常适合 作为肠道和远端组织之间的沟通模式在第一个具体目标中，我们寻求 定义动态调节 miRNA 的特征，该特征与肠道的生长和退化平行 BP 和小鼠在第二个具体目标中，我们将开发高分辨率的肠道细胞图谱。 我们提出了一种新颖的、与 BP 的生长-回归周期相关的转录组变化。 汇集尖端技术、多学科研究人员团队的变革性项目 以及一个令人着迷的新动物模型系统，它可以改变当前的研究范式并扩展当前的研究范式 研究模型，因为它提供了众多的科学和实践优势。 为进一步的机制研究奠定基础，同时它将产生独特的信息、资源和 鉴于最近的发展（例如， 基因组注释），其优点和公众的兴趣日益受到重视。