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

合作研究：肠道形态和功能调节的综合机制

• 批准号: 1655735
• 负责人: Todd Castoe
• 金额: $ 51.25万
• 依托单位: University of Texas at Arlington
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1655735&HistoricalAwards=false
• 关键词: Collaborative; Research; Integrated; mechanisms; underlying

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.

小肠是从食物中吸收营养的主要门户，食物是人体最大的内分泌和免疫器官，它拥有一个巨大的细菌群落，被认为影响身体生理的所有领域。肠道也可以重塑其结构和功能，以匹配食物的大小，适应饮食的变化，并补偿因疾病或手术而造成的损失，但目前对这种重塑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能够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，而是利用一些蛇(蟒蛇、蟒蛇和响尾蛇)的极端能力来在每顿饭中重塑它们的小肠。通过比较定期进食和零星进食的蛇之间以及蛇和其他脊椎动物之间的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，这项研究计划将为脊椎动物肠道重塑的基础机制提供新的见解。这项研究的一个令人兴奋的新颖性是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，这可能对推动肠道疾病治疗的新发现很重要。该项目的推广部分包括关于基因表达数据生成和分析的研讨会，以及对当地学校、营地和博物馆的公开讲座和基于动物的展览。脊椎动物具有改变肠道功能的生理能力，这种能力与它们的食性相适应。例如，在大餐之间自然经历长时间禁食的物种(例如，坐着等待觅食的蛇)在进食时会经历肠道形态和功能的快速上调，以及随后的肠道萎缩和消化后的下调。相比之下，经常进食的物种(例如，积极觅食的蛇)每顿饭的肠道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隘地调节肠道功能的脊椎动物中共享。通过利用蛇和其他脊椎动物在肠道反应中表现出的极端范围，以及最近可用的基因组资源，这项研究计划将确定肠道灵活性和。测试这些机制是否在谱系和调节表型之间共享。这一目标将通过追求三个目标来实现：(1)确定肠道形态调控的细胞和结构机制，以及肠道形态是否决定肠道功能的调节；(2)将转录和翻译后机制与肠道结构和功能的表型变化联系起来；以及(3)测试共有的或独特的一套分子机制是否在脊椎动物中驱动类似的表型反应。最终，这项研究将确定脊椎动物调节肠道形态和功能的信号和结构机制。

项目成果

Vertebrate Lineages Exhibit Diverse Patterns of Transposable Element Regulation and Expression across Tissues

• DOI: 10.1093/gbe/evaa068
• 发表时间: 2020-04
• 期刊: Genome Biology and Evolution
• 影响因子: 3.3
• 作者: G. M. Pasquesi;B. W. Perry;Michael W. Vandewege;Robert Ruggiero;Drew R. Schield;T. Castoe

Viral CpG Deficiency Provides No Evidence That Dogs Were Intermediate Hosts for SARS-CoV-2

• DOI: 10.1093/molbev/msaa178
• 发表时间: 2020-09-01
• 期刊: MOLECULAR BIOLOGY AND EVOLUTION
• 影响因子: 10.7
• 作者: Pollock, David D.;Castoe, Todd A.;Goldstein, Richard A.
• 通讯作者: Goldstein, Richard A.

Novel ecological and climatic conditions drive rapid adaptation in invasive Florida Burmese pythons

• DOI: 10.1111/mec.14885
• 发表时间: 2018-12-01
• 期刊: MOLECULAR ECOLOGY
• 影响因子: 4.9
• 作者: Card, Daren C.;Perry, Blair W.;Castoe, Todd A.
• 通讯作者: Castoe, Todd A.

Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals

• DOI: 10.1073/pnas.1906117116
• 发表时间: 2019-12-17
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Casewell, Nicholas R.;Petras, Daniel;Turvey, Samuel T.
• 通讯作者: Turvey, Samuel T.

Origins, genomic structure and copy number variation of snake venom myotoxins

• DOI: 10.1016/j.toxicon.2022.06.014
• 发表时间: 2022-07-12
• 期刊: TOXICON
• 影响因子: 2.8
• 作者: Gopalan, Siddharth S.;Perry, Blair W.;Castoe, Todd A.
• 通讯作者: Castoe, Todd A.