Determinants of metabolic plasticity in vertebrates

细胞能量对生命是必不可少的，在分子、生化和生物水平上，识别协调其合成和利用的调控途径是一个错综复杂的难题。在生态生理学的背景下，这些调节机制的适当调节对于物种在其环境中的驯化和生存至关重要。生物体面临的一个特别复杂的问题是维持线粒体的功能，因为这个细胞器的各种成分要么编码在核上，要么编码在线粒体基因组上。因此，为了制造一个有功能的细胞器，来自这两个基因组的数百个基因的表达必须受到协调调控。在哺乳动物中，这种协调是错综复杂的，涉及过多的转录因子及其辅助激活因子。然而，虽然已经在哺乳动物身上进行了广泛的研究，但对其他类群中的这些机制知之甚少。特别是，以前的研究表明，其他脊椎动物(如鱼类)在线粒体表型调控方面存在根本差异。我研究的长期目标是了解代谢可塑性的机制，以及它们是如何被招募来对发育和环境线索做出反应的。此外，我对脊椎动物中这些调控网络的动态进化轨迹很感兴趣。我的研究项目采用一种综合的方法来研究这些将分子过程(基因表达)与组织和整个动物新陈代谢联系起来的调控模式。具体地说，我将使用三种互补的方法来研究基因表达的关键调控因素及其在确定代谢表型中的作用。首先，我将在斑马鱼中使用有针对性的基因操作来直接评估其中一种调控因子PGC-1b在建立和调节代谢表型方面的作用。这些研究将集中在PGC-1b参与调节有氧表型的发展及其对温度和运动训练的可塑性。其次，我将把这些对调节途径的研究扩展到一种基础脊椎动物--银鳗，为代谢调节的进化提供独特的见解。最后，使用一个新的模型系统，攀爬虎鱼，我们将评估一组调节剂在两个代谢表型和物种分布不同的密切相关物种的肌肉有氧表型的发展和维持中的参与。这些研究将补充我的计划，为需氧表型的个体发育提供更多的见解，并允许在更精细的进化规模上调查这些调控差异。使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方面的根本分歧。

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.