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

项目总结 二十世纪的丹麦生理学家奥古斯特·克罗写道：“对于如此大量的问题 将会有一些动物可以选择，或者几个这样的动物，在上面它可以是最方便的 研究过了。“近50年后，生物化学家汉斯·克雷布斯将其正式命名为“克罗原理”。 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调查 为生物医学研究提供巨大价值，特别是因为它们拥有独特的功能，可以 对发生在人类身上的功能和功能障碍的前所未有的洞察。我们援引克罗的 将嘴孵化罗非鱼作为一种创新的创新鱼类 代谢调节和代谢失调研究的动物模型。在人类中， 摄食行为和代谢率的不适当脱钩显然是不适应的，严重的 在没有医疗干预的情况下危及患者的生活质量甚至生存结果。伯顿沙门氏菌 雌性在孵化幼崽时会经历长达30天的自我诱导饥饿 嘴--繁殖的先决条件--但仍能恢复进食并重新进入 繁衍周期后，它们的幼崽都实现了独立。与人类的状态不同，这些 鱼提供了一种动物模型，在这种模型中，潜在的机制是由自然形成的 并且可以方便地进行研究。这项提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：建立伯顿拟罗非鱼作为研究厌食症的动物模型， 更广泛地说，是食欲/代谢调节。根据新陈代谢测量和组织学，神经和 外围电路通过活动的表达在解剖学上定义并在功能上寻址 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进行测试 用qPCR补充基于发现的标签序列的候选神经和外周机制 分析馈入回路中已识别的大脑核团的神经转录本，从而识别 保守和新颖的摄食调节和瘦肉组织分解代谢机制。机制： 硬骨鱼和哺乳动物之间的食欲调节似乎在很大程度上是保守的， 允许进行许多直接的比较。然而，足够的系统发育距离和差异 选择性压力预示着A.burtoni的机械性适应，这在哺乳动物中是不存在的。 这些相似和不同之处可以为两种新的治疗方法提供信息，以摧毁人类 精神错乱。

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.