The Platelet Derived Growth Factor (PDGF) and its receptor mediate critical intercellular signaling which is required in multiple tissues during embryogenesis and thus loss of PDGF function is lethal in mice. Moreover, PDGF has been implicated in the formation of several types of neoplasia. PDGF signaling can produce a variety of cellular responses such as proliferation, morphogenesis, differentiation, migration, and protection from apoptosis, depending on the tissue in which it is expressed. The activated PDGF receptor interacts with multiple signal transduction proteins, however, it is not clear how their functions are coordinated to produce the distinct responses to PDGF in a regulated manner. A better understanding could be gained by the identification of genes activated in specific tissues by PDGF. The primary goal of this fellowship is to identify transcriptionally regulated targets of PDGF utilizing a gene trap screen in mouse embryonic stem (ES) cells. Briefly, this approach is based on the ability to detect the activity of a reporter gene when it is inserted in the proper orientation at a transcriptionally active site. Trapped genes can be identified in ES cells that are only expressed when PDGF is present. Once identified, the expression pattern of trapped genes can be determined in wild type embryos as well as in mice harboring mutations in the PDGF signaling machinery. This analysis should identify trapped genes that are expressed in specific tissues known to require PDGF signaling for proper development and determine which component of PDGF signaling activates the trapped gene. Furthermore, biochemical and cell biological experiments can be performed in cultured cells to elucidate the cellular role of the gene. Finally, ES cells harboring trapped genes can be used to make mutant mice to further determine the role of the trapped gene in mouse development. Given the evidence that unregulated PDGF expression can lead to neoplasia, identification of these downstream genes and determining their functions should also provide insight into the mechanisms of cancer.
| Schneider, Stefan; Iannotti, Ronald J; Nansel, Tonja R et al. (2009) Assessment of an illness-specific dimension of self-esteem in youths with type 1 diabetes. J Pediatr Psychol 34:283-93 |
| Botello-Harbaum, M; Nansel, T; Haynie, D L et al. (2008) Responsive parenting is associated with improved type 1 diabetes-related quality of life. Child Care Health Dev 34:675-81 |
| Klinghoffer, Richard A; Hamilton, T Guy; Hoch, Renee et al. (2002) An allelic series at the PDGFalphaR locus indicates unequal contributions of distinct signaling pathways during development. Dev Cell 2:103-13 |
