Collaborative Research: Integrative mechanisms underlying the regulation of intestinal form and function

小肠是人体从食物中吸收营养的主要通道，是人体最大的内分泌和免疫器官，并拥有一个巨大的细菌群落，被认为影响人体生理的所有领域。肠道也可以重塑其结构和功能，以适应食物的大小，适应饮食的变化，并补偿因疾病或手术造成的损失，但目前对这种重塑背后的确切机制知之甚少。这项合作研究的最终目标是确定使脊椎动物肠道调节结构和功能的信号和结构机制。这个项目不是依靠传统的实验室研究动物来实现这一目标，而是利用了一些蛇（蟒蛇、蟒蛇和响尾蛇）在每次进食时重塑小肠的极端能力。通过比较经常进食和偶尔进食的蛇以及蛇和其他脊椎动物之间小肠对进食和禁食的细胞和分子反应，再加上现有的基因组资源，本研究计划将为脊椎动物肠道重塑的机制提供新的见解。这项研究的一个令人兴奋的新颖之处在于纳入了非传统模式物种（即蛇），这些物种有可能揭示以前未知或被忽视的机制，并且可能对推动肠道疾病治疗的新发现很重要。该项目的外联部分包括基因表达数据生成和分析的研讨会，以及在当地学校、营地和博物馆举办的公开讲座和动物展览。脊椎动物具有改变肠道功能的生理能力，这与它们的摄食习惯有适应性的联系。例如，在大餐之间自然经历长时间禁食的物种（例如，静坐等待觅食的蛇）在进食时肠道形态和功能会迅速上调，随后在消化后肠道萎缩和下调。相比之下，频繁进食的物种（例如，主动觅食的蛇）在每顿饭中肠道的形态和功能只有轻微的变化。目前尚不清楚肠道结构和功能灵活性背后的细胞和分子机制，以及这些机制是否在广泛或狭窄地调节肠道性能的脊椎动物中共享。通过利用蛇和其他脊椎动物表现出的肠道反应的极端范围，以及最近可用的基因组资源，本研究计划将确定肠道灵活性和肠道适应性的潜在机制。测试这些机制是否在谱系和调节表型中共享。这一目标将通过以下三个目标来实现：(1)确定肠道形态调节的细胞和结构机制，以及肠道形态是否决定了肠道功能的调节；(2)将肠道结构和功能的表型变化与转录和翻译后机制联系起来；(3)检验在脊椎动物中是否有共同的或独特的分子机制驱动相似的表型反应。最终，本研究将确定脊椎动物调节肠道形态和功能的信号传导和结构机制。

The small intestine is the principal gateway for the uptake of nutrients from meals, the largest of the body's endocrine and immune organs, and hosts an immense bacterial community that is thought to influence all realms of the body's physiology. The intestine also can remodel its structure and function to match meal size, to accommodate changes in diet, and to compensate for loss due to disease or surgery, but little is currently known about the precise mechanisms that underlie this remodeling. The ultimate goal of this collaborative research is to identify the signaling and structural mechanisms that enable the vertebrate intestine to modulate structure and function. Rather than relying on traditional laboratory research animals to achieve this goal, this program takes advantage of the extreme ability of some snakes (pythons, boas, and rattlesnakes) to remodel their small intestine with each meal. By comparing the cellular and molecular responses of the small intestine to feeding and fasting among snakes that feed regularly versus sporadically, and between snakes and other vertebrates, coupled with available genomic resources, this research program will provide new insight into the mechanisms that underlie intestinal remodeling in vertebrates. An exciting novelty of this research is the incorporation of non-traditional model species (i.e., snakes) that have the potential to reveal previously unknown or overlooked mechanisms and that may be important for driving new discoveries for the therapeutic treatment of intestinal diseases. The project's outreach components include workshops on the generation and analyses of gene expression data, and public lectures and animal-based exhibitions to local schools, camps, and museums.Vertebrates possess the physiological capacities to alter intestinal performance that are adaptively linked to their feeding habits. For example, species that naturally experience long episodes of fasting between large meals (e.g., sit-and-wait foraging snakes) experience rapid upregulation of intestinal form and function with feeding, and subsequent intestinal atrophy and downregulation following digestion. In contrast, frequently feeding species (e.g., active-foraging snakes) experience only modest change in intestinal form and function with each meal. Currently unknown are the cellular and molecular mechanisms that underlie the structural and functional flexibility of the intestine, and whether such mechanisms are shared across vertebrates that widely or narrowly regulate intestinal performance. By leveraging the extreme range in intestinal responses exhibited by snakes and other vertebrates, and recently available genomic resources, this research program will identify the underlying mechanisms of intestinal flexibility and. test whether these mechanisms are shared across lineages and regulatory phenotypes. This goal will be accomplished by pursuing three aims: (1) identify the cellular and structural mechanisms that underlie the modulation of intestinal form, and whether form dictates the regulation of intestinal function; (2) link transcriptional and post-translational mechanisms to phenotypic changes in intestinal structure and function; and (3) test whether shared or unique sets of molecular mechanisms drive similar phenotypic responses among vertebrates. Ultimately, this research will identify the signaling and structural mechanisms by which vertebrates modulate intestinal form and function.