Determinants of metabolic plasticity in vertebrates

细胞能量对生命至关重要，在分子、生物化学和有机体水平上，确定协调其合成和利用的调节途径是一个复杂的难题。在生态生理学的背景下，这些调节机制的适当调节对物种在其环境中的适应和生存至关重要。生物体面临的一个特别复杂的问题是线粒体功能的维持，因为这个细胞器的各种成分要么在核上编码，要么在线粒体基因组上编码。因此，为了制造一个功能性的细胞器，来自两个基因组的数百个基因的表达必须得到协调调节。在哺乳动物中，这种协调是复杂的，涉及过多的转录因子和它们的辅激活因子。然而，尽管在哺乳动物中进行了大量的工作，但对其他分类群的这些机制知之甚少。特别是，先前的研究表明，在其他脊椎动物（如鱼类）中，线粒体表型的调节存在根本分歧。我研究的长期目标是了解代谢可塑性的机制，以及它们是如何响应发育和环境线索而被招募的。此外，我对这些调节网络在脊椎动物中的动态进化轨迹很感兴趣。我的研究项目采用综合的方法来研究这些与组织和整个动物代谢相关的分子过程（基因表达）的调节模式。具体来说，我将使用三种互补的方法研究基因表达的关键调节因子及其在决定代谢表型中的作用。首先，我将在斑马鱼中使用靶向遗传操作来直接评估其中一种调节剂PGC-1b在建立和调节代谢表型中的作用。这些研究将集中在PGC-1b在介导有氧表型的发展及其对温度和运动训练的可塑性方面的参与。其次，我将把这些调节途径的研究扩展到基础脊椎动物，银七鳃鳗，为代谢调节的进化提供独特的见解。最后，我们将利用一个新的模型系统——攀爬虾虎鱼，评估两种密切相关、代谢表型和物种分布不同的物种中一组调节因子在肌肉有氧表型的发育和维持中的作用。这些研究将补充我的项目，为有氧表型的个体发生提供更多的见解，并允许在更精细的进化尺度上研究这些调节差异。利用这些平行和互补的方法，我的研究将揭示脊椎动物代谢可塑性调节的根本分歧。

Cellular energy is essential to life, and the identification of the regulatory pathways orchestrating both its synthesis and utilization presents an intricate puzzle at the molecular, biochemical, and organismal levels. Within an ecophysiological context, the adequate modulation of these regulatory mechanisms is essential for the acclimatization and survival of species in their environment. A particularly complex problem facing organisms is the maintenance of mitochondrial function, as the various components of this organelle are either encoded on the nuclear or the mitochondrial genomes. Thus to make a functional organelle, expression of hundreds of genes from the two genomes must be coordinately regulated. In mammals, this coordination is intricate and involves a plethora of transcription factors and their coactivators. However, while extensive work has been performed in mammals, relatively little is known about these mechanisms in other taxa. In particular, previous research suggests fundamental divergences in the regulation of mitochondrial phenotype in other vertebrates such as fish. The long-term goal of my research is to understand the mechanisms of metabolic plasticity, and how they are recruited in response to developmental and environmental cues. Further, I am interested in the dynamic evolutionary trajectory of these regulatory networks in vertebrates. My research program takes an integrative approach to investigate these regulatory patterns relating molecular processes (gene expression) to tissues and whole animal metabolism. Specifically, I will investigate key regulators of gene expression and their role in determining metabolic phenotype using three complementary approaches. First, I will use targeted genetic manipulations in zebrafish to directly assess the role of one of these regulators, PGC-1b, in establishing and modulating metabolic phenotype. These investigations will focus on the involvement of PGC-1b in mediating the development of aerobic phenotype and its plasticity in response to temperature and exercise training. Second, I will extend these investigations of regulatory pathways to a basal vertebrate, the silver lamprey, providing unique insights into the evolution of metabolic regulation. Finally, using a novel model system, the climbing gobies, we will assess the involvement of a set of regulators in the development and maintenance of muscle aerobic phenotype in two closely related species with divergent metabolic phenotype and species distribution. These studies will complement my program by providing additional insights into the ontogeny of aerobic phenotype, as well as by allowing the investigation of these regulatory divergences at a finer evolutionary scale. Using these parallel and complementary approaches, my research will bring to light fundamental divergences in the regulation of metabolic plasticity in vertebrates.