This is an application for a K08 award for Dr. Joanna Halkias, an Assistant Professor with a joint appointment in the Department of Pediatrics at the University of California, San Francisco (UCSF), and in the Division of Neonatology at the UCSF Benioff Children's Hospital Oakland. It describes a 5-year training program for the development of an academic career with a research focus in the development of human fetal immunity. Since her appointment, Dr. Halkias has pursued additional training and mentorship in human immunology and molecular biology. Support from a K08 award would allow her to cement her expertise in these areas, and obtain additional training crucial to her professional development in clinical study design and biostatistical analysis. Dr. Halkias' goal is to establish an independent basic science laboratory to investigate the mechanisms underlying the development of the human fetal immune system and its contribution to the susceptibility of preterm infants to infection and inflammation. Inflammation is implicated in the pathophysiology of preterm labor, and is an independent predictor of most causes of death and disability in premature infants. To design better therapies for the complications associated with prematurity, we will require a better understanding of the factors that direct the development of fetal immunity. The goal of this proposal is to uncover the cellular and molecular mechanisms by which placental hormones shape fetal T cell immunity, a critical modulator of the fetal inflammatory response and immune-mediated injury in preterm infants. Dr. Halkias has adapted an innovative thymic explant model to investigate the effect of hormones on T cell development, and has identified that progesterone is involved in the reciprocal regulation of specialized populations of human fetal T cells. In this proposal, Dr. Halkias aims to expand on her findings and determine whether estrogen enhances the effect of progesterone on T cell development in the thymus as well as T cell activation in the periphery. She will elucidate the mechanism by which progesterone influences fetal T cells by dissecting the contribution of rapid signaling by membrane receptors, as well as the classic, genomic effects of nuclear receptors. Lastly, she will evaluate the effect of antenatal progesterone therapy on infant T cell immunity and inflammation. Dr. Halkias' primary mentor is Dr. Susan Fisher, Professor of Obstetrics, Gynecology and Reproductive Sciences, and an expert in placental biology and developmental stem cell biology. Her co- mentor, Dr. Joseph (Mike) McCune, Professor of Medicine, is an expert in infectious disease and human immune system ontogeny. She has also established a team of collaborators who will provide expertise in maternal-fetal medicine, hormone signaling and metabolism, and signal transduction pathways. An advisory committee will provide formal input on a quarterly basis to ensure Dr. Halkias' success, productivity, and career progress to support her transition to an independent researcher eligible for R01 funded studies.
Premature infants, born before 37 weeks of gestation, suffer a disproportionately high rate of death and disability. The complications associated with prematurity represent a significant public health burden that can result in long-term social, educational, and health associated costs. The unique developmental state of the premature infant's immune system causes it to respond inappropriately to both infection and life-saving invasive care, resulting in many of the complications associated with being born too soon. What causes this aberrant immune response in premature infants is poorly understood. Determining the factors that influence the development of the fetal immune response will help to identify preventive and treatment strategies specific for the premature infant, and will help to avoid or reduce the complications associated with prematurity.