This is a new proposal to study the peri-implantation development of the mammalian embryo, with particular emphasis on the morphogenetic events that are critical for implantation and successful pregnancy. The purpose of the program, which consists of six projects, is to study genes that are essential for implantation by defining their expression and role of their products in normal and abnormal peri-implantation development, and thus, to achieve a basic understanding of the mechanisms of the complex interactions between the embryo and uterus that are necessary for embryonic survival and growth and the maintenance of early pregnancy. These problems will be studied with state-of-the-art morphological, immunological, cellular and molecular technologies to reveal the nature of gene expression essential for peri-implantation mouse and human development using several distinct, but complementary, approaches. The first project studies the distribution and function of two classes of cell surface-extracellular matrix adhesion molecules, integrins and cell surface proteoglycans in embryos and cell culture models. The second project identifies and characterizes the developmental regulation of proteases involved in the process of invasion by human trophoblast. The third project identifies and characterizes growth factors and receptors that are expressed in peri-implantation mouse embryos. The fourth project analyzes the expression and role of growth factors, their receptors and proto-oncogenes involved in signal transduction in the normal human placenta and the hydatidiform mole (androgenote). The fifth project examines the development of peri- implantation recessive lethal mutants, and characterizes monosomies for mouse chromosomes 2, 6, 7, 11, or 17 to determine the identity of genes affected by these conditions. The sixth project analyzes the genetic basis for the developmental failure of mouse parthenogenotes and androgenotes. The administrative core will provide organizational activities to enhance the interaction between investigators. The antibody core will be responsible for generating antibodies against antigens purified by the investigators. The morphology/in situ localization core will be responsible for conducting light and electron microscopic histology, immunohistochemistry and localization of messenger RNA by in situ hybridization of mRNA. The transgenesis/stem cell core will be responsible for producing transgenic lines of mice, and for carrying out targeted gene mutation by homologous recombination in embryonic stem cells. The focus on a combination of mouse and human trophoblast development will strengthen the generality of the conclusions from these studies. This comparative approach should make possible the application of new concepts to clinical problems, such as prenatal diagnosis, detection and treatment of trophoblast neoplasia, and treatment of infertility.
Showing the most recent 10 out of 78 publications
