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: 10042881
• 负责人: Nima Saeidi
• 金额: $ 27.94万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042881
• 关键词: Animal Model; Atlases; Atrophic; Biogenesis; Biological Models; Blood Circulation; Burmese; Cell Nucleus; Clinical; Communication; Comparative Study; Critical Illness; Data; Data Set; Development; Diabetes Mellitus; Disease; Distal; Exposure to; Fasting; Foundations; Funding Opportunities; Gastric Bypass; Gene Expression; Gene Expression Profiling; Genetic Transcription; Glucose; Growth; Habits; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Home environment; Homeostasis; Hour; Human; Institutes; Institution; Intestinal Bypasses; Intestinal Neoplasms; Intestines; Laboratories; Malignant Neoplasms; Mammals; Mediating; Metabolic; MicroRNAs; Modeling; Molecular; Mus; Nutrient; Obesity; Organ; Organ Size; Pathologic; Pathologic Processes; Pathway interactions; Pattern; Phase; Physiological; Process; Pythons; Regression Analysis; Regulation; Reptiles; Research; Research Personnel; Resolution; Resources; Rodent; Role; Sampling; Signal Transduction; Small RNA; Starvation; Stimulus; Study models; Technology; Testing; Therapeutic; Time; Tissues; United States National Institutes of Health; Untranslated RNA; adverse outcome; comparative; deep sequencing; effective therapy; fascinate; feeding; functional adaptation; genome annotation; heart dimension/size; heart function; improved; innovation; insight; interest; metabolic abnormality assessment; multidisciplinary; novel; obesity treatment; organ growth; organ regeneration; pressure; programs; rapid growth; response; transcriptome sequencing; transcriptomics

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.

项目摘要 在这个项目中，我们将研究缅甸蟒蛇（BP），一种快速，大规模，控制和 不断的器官生长几项研究表明，与实验室哺乳动物和人类不同， 自然地不经常进食，它们的进食习惯与快速和大规模的调节有关。 反应和器官生长，随后是消化后回归阶段。这种独特的模式可以 提供有关潜在的适应性，有益的，精心策划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 适应不良的肥大性或萎缩性疾病状态。在拟议的研究中，我们希望开发一个更深入的 特别是对肠道适应的机械理解。通过研究生长阶段， 在进食后的一段时间里，我们可以发现那些驱动肠道和其他器官的机制， 从休眠状态到完全功能。回归阶段的分析将为我们提供 关于机制的宝贵信息，这些机制可能起到“刹车”的作用，阻止增长。该项目建立 我们对啮齿动物、蟒蛇和人类的初步比较研究， 保守的肠道特征和关键的调控网络。物种之间的比较研究是 强大的和共同的，进化保守的机制目标，过程和途径的发现 为调查结果的重要性提供了进一步的信心。这些差异可能代表着机会， 利用，通过尝试在哺乳动物中重现，例如，转录组模式， 在BP中是不同的。我们的数据突出了microRNAs（miRNAs）的作用，它们是小的非编码RNA。 在转录后水平调节基因表达的RNA。他们是优秀的候选人， 调节肠道适应性过程的可塑性，因为它们是肠道稳态的主要调节剂 和许多功能。此外，由于miRNA可以在循环中分泌，因此它们非常适合于 作为肠道和远端组织之间的交流方式。在第一个具体目标中，我们力求 定义了一个动态调节的miRNAs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，我们将开发一个高分辨率的肠道细胞图谱， 转录组学变化与BP的生长-消退周期相关。我们要写一部小说， 一个变革性的项目，汇集了尖端技术，一个多学科的研究团队， 以及一个迷人的新动物模型系统，它可以改变当前的研究范式， 研究模型，因为它提供了许多科学和实用的优势。它将启用并设置 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 有价值的数据集。我们预计，考虑到最近的发展（例如， 基因组注释）、其日益受到赞赏的优点以及普通公众的兴趣。