This proposal centers on intrauterine growth restriction (IUGR), which causes early neonatal morbidity and mortality, and is implicated in developmental delay and neurobehavioral dysfunction during childhood. Moreover, inadequate embryonic growth is associated with metabolic disorders during adult life, including hypertension, coronary artery disease, hypeflipidemia and insulin resistance. Intact placental function depends on villous trophoblast at the feto-maternal interface, which fulfills critical functions for embryonic development, including gas exchange, supply of nutrients and removal of waste products, endocrine regulation and immunological defense. Diverse physical, chemical and biological stressors adversely influence the homeostatic balance between trophoblast injury, adaptation and regeneration, resulting in placental dysfunction and substandard fetal growth. This proposal is a part of our continuing effort to further our knowledge of molecular mechanisms that underlie trophoblast injury and adaptation. We surmise that placental under-perfusion, and consequently cellular hypoxia, impacts the expression of a unique set of trophoblast genes, resulting in a major villous insult. With the complete sequencing of the human genome, the discovery of shared factors that cause a disease or influence its course is now within reach. The employment of high-throughput screens such as oligonucleotide microarray is particularly useful for complex diseases such as IUGR, where a composite set of gene products determines pathogenesis, modulates tissue response to insult and may even serve as a target for future gene therapy. Using a novel approach to gene expression analysis we determined that connective tissue growth factor and follistatin-related gene are highly regulated by hypoxic trophoblasts. We hypothesize that these glycoproteins are co-regulated by hypoxia in trophoblasts, and mediate trophoblast response to hypoxic injury. Although previously unexplored in the context of placental biology, these functionally clustered growth factors are poised to regulate trophoblast injury and repair. Utilizing cutting-edge tools we establish the expression of these growth factors in hypoxic trophoblasts, dissect their function and analyze their regulation in response to hypoxia. Conclusions from our studies are likely to shed light on the mechanisms of villous injury, and may provide new tools to identify and manage IUGR and its sequelae. ? ?
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