Grant: Discovery Grants Program - Individual

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.