The Muglia Laboratory seeks to define the mechanism controlling the timing for birth in humans. The composition of the biological clock metering the duration of human gestation remains a central question in reproductive biology.
How Does the Timing Machinery Work?
The primary goal is to understand the molecular timing machinery comprising this biological clock to prevent or better treat human preterm labor. Our laboratory has generated and analyzed mice with defects in prostaglandin biosynthesis, prostaglandin catabolism and oxytocin production in efforts to begin to define the key physiological pathways.
These, and other, genetic studies in mice reveal an essential function for cyclooxygenase-1-generated prostaglandin F2 alpha for labor onset, and the degrading enzyme hydroxyprostaglandin dehydrogenase in the maintenance of pregnancy. Recent efforts analyze the contribution of genetic determinants to preterm birth in humans.
We have begun to analyze DNA from families with recurrent preterm birth and control families without preterm infants through genome-wide association and candidate gene studies. Identification of novel contributors to human preterm birth has been revealed by genetic epidemiological and comparative genomic methods. The wealth of comparative genomic information now available will lead to new insights into genes involved in human preterm birth.
We have found that genes involved in preterm birth have evolved rapidly along the human lineage and can be identified by an increased rate of protein evolution or an increased rate of gain or loss of transcription factor binding sites relative to other mammals. In addition to these studies, longitudinal metabolic profiling of women at high risk for preterm birth is being initiated using high-dimensional mass spectroscopy / NMR techniques.
Understanding Responses to Stress
A second area of investigation is to elucidate the molecular pathways involved in the behavioral and neuroendocrine responses to stress, and to determine how these mechanisms affect development and aging. Importantly, chronic stress often results in alterations in behavior and physiology that are maladaptive, exacerbating both medical and psychiatric diseases.
The Muglia Laboratory has analyzed mice with corticotropin-releasing hormone (CRH) deficiency to determine the role of this hypothalamic neuropeptide in adrenal axis regulation and fetal development. These studies demonstrated a critical role for CRH in promoting glucocorticoid secretion during metabolic and psychological stressors, and for glucocorticoids in promoting normal lung development.
To definitively determine the importance of glucocorticoids on specific immune cell populations and in the brain, we have generated mice with conventional and conditional tissue-specific inactivation of the glucocorticoid receptor. These studies have revealed an essential role for the glucocorticoid receptor to limit inflammatory responses after immune cell activation, and modify anxiety, learning and memory. Ongoing efforts seek to elucidate subregion specific actions of glucocorticoid receptors and adenylyl cyclases by combining homologous recombination and gene therapy approaches in mice.