Mouth-brooding: a teleost adaptation as atractable model of metabolic disorder

项目摘要 20世纪丹麦生理学家奥古斯特·克罗（August Krogh）写道，“对于如此大量的问题， 会有一些动物的选择，或几个这样的动物，它可以最方便地 研究”。近50年后，生物化学家汉斯·克雷布斯（Hans Krebs）将其正式命名为“克罗格原理”， 方法已经成为许多科学领域的指导租户，例如比较生理学， 神经行为学和功能基因组学。对这种远亲模式生物的研究 为生物医学研究提供了巨大的价值，特别是因为它们具有独特的功能， 对人类功能和功能障碍的前所未有的洞察。我们援引克罗的 原则，以推进口育雏慈鲷鱼Astatotilapia burtoni作为一个创新的 用于研究代谢调节和失调的动物模型。人类的 摄食行为和代谢率的不适当脱钩显然是不适应的， 在没有医疗干预的情况下损害患者的生活质量甚至生存结果。A.伯托尼 雌性经历长达30天的自我诱导饥饿，同时在其 嘴-繁殖的先决条件-但恢复恢复进食和重新进入 繁殖周期后，他们的年轻人已经取得了独立。与人类相比，这些 鱼类提供了一种动物模型，其中潜在的机制已经被自然环境塑造， 选择，可以方便地学习。该建议的协同目标跨越生理， 基因调控网络、蛋白质表达、组织组织学、调控神经回路分析，以及 药理学以建立适合于厌食症研究的动物模型， 更广泛地说，食欲/代谢调节。在代谢测量和组织学检查后， 外周回路在解剖学上被定义，并通过活动的表达在功能上被处理 标记物、放射自显影和药理学。最后，我们使用假设驱动的方法来测试 用qPCR补充基于发现的Tag-Seq的候选神经和外周机制 分析来自所述进食回路中所识别的脑核团的神经转录组，从而识别 保守的和新的机制，喂养调节和瘦肉组织catastrophic。机制 食欲调节似乎在硬骨鱼和哺乳动物谱系之间基本上是保守的， 允许许多直接比较。然而，足够的系统发育距离和差异， 选择性压力预测了A.在哺乳动物中不存在的Burtoni。 这些相似性和差异可以为两种新的治疗方法提供信息，以毁灭性的人类 紊乱

PROJECT SUMMARY Twentieth-century Danish physiologist August Krogh wrote that, “for such a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied.” Formalized as “Krogh's Principle” by biochemist Hans Krebs nearly 50 years later, this approach has become a guiding tenant for many scientific fields such as comparative physiology, neuroethology, and functional genomics. Investigations in such distantly-related model organisms provide great value to biomedical research specifically because they possess unique features that allow unprecedented insight to functions and dysfunctions that occur in humans. We invoke Krogh's principle to advance the mouth-brooding cichlid fish Astatotilapia burtoni as an innovative animal model for the study of metabolic regulation and dysregulation. In humans, the inappropriate decoupling of feeding behavior and metabolic rate is clearly maladaptive, severely compromising patient quality of life and even survival outcome without medical intervention. A. burtoni females undergo self induced starvation for as long as 30 days while brooding their young in their mouths - a prerequisite of reproduction - and yet recover to resume feeding and reenter the reproductive cycle after their young have achieved independence. In contrast to the human state, these fish provide an animal model in which the underlying mechanisms have been shaped by natural selection and can be conveniently studied. The synergistic aims of this proposal span physiological, gene regulatory networks, protein-expression, tissue histology, regulatory neural circuit analysis, and pharmacology to establish Astatotilapia burtoni as an animal model suited to the study of anorexia and, more broadly, appetite/metabolic regulation. Following metabolic measures and histology, neural and peripheral circuits are anatomically defined and functionally addressed through expression of activity markers, autoradiography, and pharmacology. Finally, we use a hypothesis-driven approach to test candidate neural and peripheral mechanisms with qPCR to complement a discovery-based Tag-Seq analysis of neural transcriptomes from identified brain nuclei in the feeding circuit, thereby identifying conserved and novel mechanisms of feeding regulation and lean tissue catabolism. Mechanisms of appetite regulation appear to be largely conserved between the teleost and mammalian lineages, allowing for many direct comparisons. However, sufficient phylogenetic distance and difference in selective pressures predict mechanistic adaptations in A. burtoni that are not present in mammals. These similarities and differences can inform both novel therapeutic approaches to devastating human disorders.