NIH opportunities (2) – Trophoblast Differentiation and Function (R01, R21)

September 27, 2016 by School of Medicine Webmaster

The description below was taken from the R01 version of this FOA.

The placenta nourishes and protects the conceptus from the time of embryo implantation through parturition by functioning as the gut, the lung and the kidney of the growing fetus. The placenta has to develop and function in parallel with the growth of the conceptus. Hence, normal functioning of this organ is critical to fetal development and well-being. Unfortunately in the early stage of pregnancy only one half of embryos/placentas develop and grow to their full size with good function. Frequently early embryonic loss takes place within the first 2 weeks of gestation due to placentation failure.

Adequate maternal blood supply to the placenta is essential. The proper functioning of the placenta is often disrupted due to the lack of the invading trophoblast to sufficiently remodel the uterine spiral arteries into low-resistance, high-capacity vessels to provide sufficient maternal blood to the placenta, and can lead to preeclampsia, fetal growth restriction and preterm birth.

The placenta is primarily composed of trophoblast cells. The trophoblast cells of the placenta arise from the trophectoderm of the embryo at the blastocyst stage. At the time of implantation trophoblast cells attach to the luminal epithelium of the uterus and invade the endometrial tissues. At the same time these invading trophoblast cells differentiate and gain various functions to form the placenta as well as to establish pregnancy in the uterus. During the early stages of pregnancy there are continuous interactions between trophoblast cells and the maternal tissue components in order for the embryo to obtain oxygen and nutrients to develop and survive before the placenta is fully established. During this process of placentation, interactions between trophoblast and maternal tissues are critical for normal placentation.

In addition, the placenta plays an important immunomodulatory role in the establishment and maintenance of pregnancy. A successful pregnancy involves complex interactions between fetal trophoblasts and maternal decidual immune cells, which allow the embryo and then fetus to develop in the uterus without triggering the mother’s immune response against the embryo/fetus. Uterine natural killer cells, immature dendritic cells, T cells and macrophages contribute to modulating the uterine environment to sustain a successful pregnancy. As pregnancy progresses, immunologic changes occur increasing the risk of maternal morbidity and mortality associated with certain pathogens such as Listeria monocytogenes and influenza virus. Inflammation is associated with poor pregnancy outcomes such as preterm birth, stillbirth and fetal injury. However, the immune mechanisms by which infections induce placental dysfunction remain to be determined.

We have very little knowledge as to how uterine cells interact with invading trophoblast. Thus, knowledge is needed in how trophoblast and uterine cells communicate throughout pregnancy. Specifically, sufficient knowledge is lacking in four areas: (1) What essential molecules are involved in the successful implantation process and what molecule(s) may be useful to diagnose implantation failure including frequent pregnancy loss? (2) How do trophoblast and uterine cells interact to facilitate the remodeling of uterine spiral arteries? (3)What are the critical regulatory mechanisms of trophoblast differentiation and function? (4) How do inflammatory responses in the placenta contribute to poor placental development?

Research Objectives

A major goal of this FOA is to stimulate research that will broaden our understanding of how trophoblast cells differentiate and function with respect to their interaction with maternal cells/tissues. Starting from the time of blastocyst implantation through placentation, trophoblast cells interact with uterine luminal epithelium, stromal cell, decidual cells, immune cells, blood vessels and other uterine components. Research on human trophoblasts is ideal; experimental animal studies are acceptable to enhance our understanding of human trophoblast differentiation and function.

Research topics encouraged by this FOA include, but not limited to, the following:

  • Determining the genetic and epigenetic aspects of trophoblast differentiation and function
  • Clarifying the mechanisms involved in differentiation from cytotrophoblast to syncytiotrophoblast, particularly around the time of implantation as well as at villus formation and maturation
  • Understanding how some trophoblasts differentiate into villous cytotrophoblasts, extravillous cytotrophoblasts and other trophoblast cell types
  • Elucidating the role of endovascular trophoblast cells
  • Clarifying the mechanisms involved in interactions between trophoblast and maternal tissues,       including exosomes, ligand-receptors, cell surface molecules and cell polarity.
  • Determining the endocrine and immune functions of trophoblast cells around the time of physiologically distinct stages of pregnancy such as implantation, placental establishment and parturition, as well as under pathophysiological conditions such as implantation failure, preeclampsia, preterm birth etc.
  • Understanding the regulatory mechanisms involved in insufficient or excessive trophoblast penetration of maternal tissues
  • Determining the placental and host defense mechanisms involved in protecting the developing fetus from bacterial and viral infection (such as Treponema pallidum, Zika virus); novel mechanisms utilized by placental trophoblasts to resist infections locally and systemically;
  • Molecular pathways of innate and adaptive responses to infection and/or vaccines during early pregnancy; the immunologic framework of the placenta and its ability to respond to infections;
  • Immune regulatory components and mechanisms that promote infection susceptibility versus those required for sustaining pregnancy;
  • Functional and transcriptional status of uterine natural killer cells; and role of infection and/or inflammation on the development of an effective placenta
  • Developing trophoblast and uterine tissue in vitro co-culture systems to understand stage- and locus-specific interactions between trophoblast and maternal tissues/cells, including immune cells

Deadlines:  standard dates apply

URLs:

Filed Under: Funding Opportunities