LELAND STANFORD JUNIOR UNIVERSITY, THE
Grant: $312,766 - National Institutes of Health - Sep. 28, 2009
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Award Description: We have established a powerful discovery strategy to determine critical gene function and to identify and prioritize candidate downstream genes. Our strategy comprises morpholino oligonucleotide (MO)-mediated, specific gene knockdown, validation of knockdown, global gene expression profiling of pooled embryos and large-scale validation of differential gene expression at the level of the single-embryo. Using this strategy, we discovered that Oct4 has novel and critical functions during early embryo development prior to the blastocyst stage. Specifically, we found that Oct4 has a distinct and specific role in the maternal-embryonic transition, in controlling genes encoding post-transcriptional and translational regulation, in addition to its conservative functions shared amongst pluripotent cell types. The Parent Grant is currently focused on deconstructing the gene regulatory network by investigating the co- and cross-regulatory roles of Oct4 and Sall4, at each of the 2-, 4-, multi-cell, and morula stages, with a focus on genes encoding transcription factors and signaling molecules that have established functions in embryonic stem cells. We have found that many genes that are normally expressed in the early embryo, including large numbers of genes that appear to be regulated by Oct4 and/or Sall4, are generally known for essential functions restricted to, or enriched in lineage-specific tissues or cells. Yet the role of their early embryonic expression, possibly transient, has not been investigated. We hypothesize that these lineage-specific/enriched genes have distinct and critical roles during preimplantation embryo development. The overall goal of this Administrative Supplement is to identify Oct4- and/or Sall4-regulated genes that are currently only known for their lineage-specific functions later in development, and to investigate whether their expression in the early embryo is required for proper biological function during or after lineage-specific differentiation. While conventional gene-targeting models have established the genotype ? phenotype causality in developmental and many adult-onset diseases, non-genotype-based early embryonic origin of disease is not well defined or understood. Although this topic is within the scientific scope of our funded Parent Grant, this work cannot be conducted without the support of this Administrative Supplement, which is required to support the personnel, supplies and equipment that are necessary to investigate this question. Investigation of this topic would have significant impact on fundamental embryo biology as well as reprogramming mechanisms.
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