CAREER: Molecular Evolution of Steroid Hormone Receptor Function And Interactions

University Of Oregon Eugene, Eugene OR

Investigators

Abstract

CAREER: Molecular Evolution of Steroid Hormone Receptor Functions and Interactions Joseph W. Thornton University of Oregon Virtually everything that living cells do is made possible by very specific interactions between molecules. For example, steroid hormones produced in the gonads or adrenal gland-such as estrogen, testosterone, and cortisol-regulate development, reproduction, behavior, and countless other processes. Each hormone produces a unique suite of effects by binding to a specific receptor protein in target cells; the hormone-bound receptor then enters the nucleus, binds to a specific set of DNA sequences, and activates the expression of nearby genes. Despite the great biological importance of specific interactions like this, there has been very little work to understand how tight molecular partnerships evolve. This career plan integrates research on the evolution of molecular interactions with education and outreach activities that strengthen understanding of evolution, endocrinology, and the deployment of scientific knowledge in public policy. In the project's research component, steroid hormones and their receptors will be used as a model system, with the goal of reconstructing the evolutionary mechanisms by which the specific interactions between hormones and receptors evolved. First, the investigators will isolate and characterize receptors from several target species that, because of their position in the tree of life, will provide crucial information about the diversification of the receptor gene family. Phylogenetic techniques will be used to infer the dynamics by which the family diversified in number, molecular sequence, structure, and the ability to be activated by new hormones. The investigators will then test hypotheses about how receptors evolved novel functions by "resurrecting" ancestral receptor genes and studying their functions in the laboratory. Finally, experiments will be performed to determine how changes at the DNA level caused receptors to evolve new functions by re-introducing historical mutations into resurrected ancestral genes and determining their effects on the receptors' interactions with various hormones. The education and outreach components of this proposal are focused on the interface of science with real-world policy issues. A new course will be developed, which prepares young scientists to participate in societal decision-making by teaching them to think critically about the ways that science is deployed in the policy process; environmental endocrine disrupters-pollutants that interfere with the body's steroid hormones - will be used as an extended case study. A large undergraduate course in Evolutionary Biology will be revised to better incorporate the applied implications of evolutionary knowledge. Finally, the principal investigator will serve as an occasional science advisor to two nongovernmental organizations that work directly with large constituencies on environmental endocrine disruption and human health.