Trophoblast Biology: Placental Proteomics and Membrane Repair Mechanisms in Syncytiotrophoblast
The human placenta is a vital, yet transient organ that facilitates the exchange of solutes and gases between the mother and developing fetus during pregnancy. The maternal surface of the human placenta is covered by a multinucleate cellular layer, known as the syncytiotrophoblast (STB). Human placentation is such that, during the greater part of pregnancy, the apical plasma membrane of the STB interacts with maternal blood. The STB produces many of the hormones and growth factors required for successful gestation, serves as a barrier to maternal immune surveillance, and protects against maternal blood coagulation. Moreover, it is through the STB layer that all maternal-fetal exchange must occur.
In order to study this important membrane in greater detail, LPR investigators, in collaboration with Dr. John Robinson and Dr. Dale Vandre of the OSU Dept. of Physiology and Cell Biology, have developed a procedure for isolating highly enriched fractions of the STB interface. The method has enabled proteomics profiling of the STB apical plasma membrane using the mass spectrometry facility of the Campus Chemical Instrumentation Center. This profiling study has led to the identification of over 500 proteins, many of which were previously unknown in the placenta.
Through this proteomics work, two members of the ferlin protein family (dysferlin and myoferlin) were identified in the placenta. These proteins were previously known primarily from studies of skeletal muscle, and have been implicated in muscle development and the repair of damaged plasma membranes. Dysferlin and myoferlin are likely to be an important in placental biology, since the apical plasma membrane of the STB is subjected to significant membrane stress. In particular, there is likely a continuous need for repair of this membrane, because large numbers of syncytial sprouts are shed throughout normal pregnancy (and even moreso during pregnancies complicated by diseases such as pre-eclampsia). Experiments are currently underway to determine the mechanism of membrane repair in placental trophoblasts.
Racial Disparities in Preterm Birth: The SHAPE Study Group
Preterm birth (PTB) continues to be a significant public health problem. In 2006 in the U.S., more than 500,000 infants (12.8% of all births) were born preterm (before 37 completed weeks of pregnancy). Although many believe that this problem has been solved by neonatal intensive care, PTB remains the leading cause of death and disability for infants in the 1st year of life, and has life-long consequences for many preterm infants, including vision and hearing loss, poor school performance, mental retardation, and cerebral palsy. Preterm birth is almost twice as common in African American women compared to women of other racial or ethnic backgrounds, and is the reason for the increased infant mortality rates in non-Hispanic black (NHB) infants.
Given the clear need to understand the causes of PTB, which is most compelling among NHB women for whom infant mortality rates are disproportionately high, an interdisciplinary working group was established by Dr. Jay Iams. The SHAPE (Stress, Health, And the Pregnancy Experience) Study Group includes LPR members in addition to investigators from Nationwide Children's Hospital, OSU College of Nursing, OSU College of Public Health, and the Institute for Behavioral Medicine Research. A pilot study, funded through the Kirwan Institute for the Study of Race and Ethnicity , will investigate whether differential exposure to chronic psychosocial stressors (such as structural racism) contributes to the observed racial disparities in PTB rates. This study will include measurements of both psychosocial and pathophysiological stress (e.g., stress hormone levels, immune dysregulation, and inflammatory mediators) as potential contributors to PTB. It is anticipated that this study will help define specific mechanisms that contribute to the syndrome of PTB in racial minorties, and may offer targetted interventions that can be implemented as OSUMC continues towards the goal of personalized health care.
Stem Cell Biology & Regenerative Medicine
It has long been recognized that the 3-dimensional geometry of tissues influences their development in vivo. The LPR, in collaboration with Dr. John Lannutti of the College of Engineering, have been using nanotechnology strategies to model the effect of topography and geometry in tissue development for several years. Recently, a collaboration between Dr. Lannutti, Dr. Matthew Ringel (Department of Internal Medicine and Comprehensive Cancer Center), and Ruth Li, a PhD student in the LPR, has embarked on a series of studies to examine the influence of disruption signal transduction molecules (Akt-1 and MAP kinases ERK-1/2) on the migration and proliferation of breast cancer cells and embryonic stem cells. These investigations will establish a new working paradigm of cellular signaling that controls cancer cell migration as a model for tumor metastasis and epithelial-to-mesenchymal transitions during early development and tissue morphogenesis. This work is sponsored by the Nanoscale Science & Engineering Center (NSEC) awarded to Ohio State in 2004 by the National Science Foundation.
As an extension of this work towards applications in tissue engineering and regenerative medicine, the LPR has focused increasingly on the use of embryonic stem (ES) cells to model key developmental processes in organogenesis. Mouse ES cells have been shown to differentiate into a variety of cell types when cultured in medium enriched in tissue-specific growth factors, and LPR investigators have employed these cells to model the development of adipose tissue. In addition, the LPR is currently investigating the use of federally-approved human embryonic stem cell lines as an additional model system to study tissue tissue differentiation.