The goal of this proposal is to define the mechanisms by which the Foxc1 transcription factors control vascular development. Despite recent advances toward understanding genetic programming in vascular development, there are many important questions that remain unanswered. For example, the mechanisms of differential gene regulation and critical signaling pathways that are crucial for vascular formation and morphogenesis need to be determined. Members of the Fox transcription factor family, including the FoxC subfamily, have been implicated in vascular formation (Papanicolaou et al. 2008). Lack of FoxC (foxc1a and foxc1b) in zebrafish results in defects in angiogenic vessel patterning, disruptions in vascular basement membrane integrity, and increased vascular permeability, as well as arteriovenous malformations (Skarie and Link 2009). Our group has previously shown that mice deficient for the FoxC homologs (Foxc1 and Foxc2) show abnormal vessel morphogenesis/remodeling and impaired arterial cell determination (Kume et al. 2001, Seo et al. 2006). Taken together, FoxC acts as a key regulator for vascular development. Our recent analysis using mouse embryonic fibroblasts lacking Foxc2 reveals differential expression of mircoRNAs (abbr. miRNAs), which are small non-coding RNA molecules and regulate a variety of key biological processes by modulating gene expression at the transcriptional and posttranscriptional levels, including vascular development. We therefore hypothesize that the FoxC transcription factors play important roles in orchestration of transcriptional and posttranscriptional events that determine vascular phenotypes. Taken together, the central hypothesis of this project is that the FoxC transcription factors act as critical regulators in vascular formation and maintenance. This hypothesis will be tested by molecular and cellular analyses using zebrafish
|Effective start/end date||6/1/13 → 8/31/13|
- American Heart Association Midwest Affiliate (13UFEL17370016)
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