Molecular causes and physiological and behavioral consequences of extreme glucocorticoid levels in Peromyscus mice - Project Summary/Abstract Glucocorticoids (GCs) are among the most widely prescribed type of drugs in the world because of their immunosuppressive effects, but chronic, high GCs leads to adverse effects. It is thus surprising that extremely high basal GCs levels have independently evolved in mammals five times, suggesting that elevated GCs are tolerated or even beneficial under certain conditions. Although there are clear implications for glucocorticoid therapy in humans, very little is known about why high GCs have evolved or how they are tolerated. To address these questions, I turned to a pair of species that are uniquely suited to revealing the consequences of GC evolution. P. polionotus (oldfield mice) and P. maniculatus (deer mice) are closely enough related to hybridize, yet oldfield mice have a have 27 higher corticosterone (CORT) – the primary GC in rodents – in plasma than deer mice. This divergence in CORT is associated with a 6 larger of the adrenal gland – the organ which is the primary source CORT in the body. In the K99 phase, I will use these sister species to identify the biochemical causes and physiological consequences of evolution at two key genes: the glucocorticoid receptor (GR) and the corticosteroid binding globulin (CBG). During the mentored phase of this award, I will discover the biochemical consequences of protein divergence at CBG and GR on the regulation of CORT (Aim 1) and characterize the metabolic, immunological, and behavioral consequences of divergence of these genes (Aim 2). The comparison of biochemical consequences of protein divergence will allow me to characterize amino acid variants that have never been functionally tested before for their ability to regulate CORT levels and subsequently identify the phenotypic consequences of that evolution. For the independent phase of the award, I will transfer the skills and techniques acquired during the training phase to develop a new model of glucocorticoid tolerance that exhibits infection tolerance: the white-footed mouse, a major vector of Lyme disease that has convergently evolved high CORT and large adrenals (Aim 3). The proposed professional development plan under the complementary mentorship of Dr. Andrés Bendesky and Dr. Kiran Soma makes use of my expertise in genetics, behavioral evolution, and neuroscience in conjunction with new training in biochemistry and germline modification which is necessary to complete the proposed experiments and hone my research skills on the mechanisms of glucocorticoid tolerance. To achieve my goals, I have assembled an interdisciplinary team that includes experts in ligand-receptor interactions, mass spectrometry, statistical modeling of protein evolution, and germline modification, this team is ideal to train me in the techniques that will allow me to successfully complete the proposed experiments. This unique project offers the opportunity for me to develop critical training in new field in order to start my own lab exploring the significance of steroid evolution in the immune system and behavior, uniting evolutionary biology and neuroscience.
