Analysis of the expression and effects of vascular endothelial growth factor family of molecules on Fragile X Syndrome abnormalities in a mouse model

Fragile X Syndrome (FXS);Fragile X Mental Retardation Protein (FMRP);Vascular endothelial growth factor (VEGF);Autism

Belagodu, Amogh P.

关键词: Fragile X Syndrome (FXS);    Fragile X Mental Retardation Protein (FMRP);    Vascular endothelial growth factor (VEGF);    Autism;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/97769/BELAGODU-DISSERTATION-2017.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Fragile X Syndrome (FXS) is the most common form of inherited mental retardation affecting 1:3600 males and 1:8000 females (Cornish et al., 2008).The primary cause is a silencing of the FMR1 gene, via increased CGG trinucleotide repeats, which encodes for the Fragile X Mental Retardation Protein (FMRP) (Santoro et al., 2012).The current prevailing theory for the molecular mechanism mediating FXS molecular, physical, and behavioral phenotypes is centered around dysregulation of down-stream products of the metabotropic glutamate receptor (mGluR) (mGluR Theory) (Bear et al., 2004).However recent clinical trials using mGluR inhibitors have all failed, attributing to various factors such as a need for optimized dosage, developmental time for intervention, better metrics for human studies, and most prominently complexity of the mGluR pathway (Scharf et al., 2015).With this ubiquitous failure of mGluR inhibitors, new thrusts have been initiated to determine which of the downstream components of the mGluR pathway is leading to and causing FXS phenotypes.In the pursuit of isolating and determining potential causes/therapeutic targets for intervention, the current dissertation explored the role of vascular endothelial growth factor A (VEGF-A), a downstream component of mGluR.This dissertation will outline a series of studies where we demonstrate that VEGF-A is elevated in adult FXS mice and that modulation of this elevated VEGF-A can attenuate many FXS abnormalities.In Chapter 2, we obtain developmental expression profiles of the VEGF Family of molecules and their Receptors to help understand where this dysregulation occurs and how it manifests throughout development.Next, Chapter 3 we found that through blocking VEGF-A, Synapsin-1 levels (a presynaptic marker) were reduced to wildtype (WT) levels and resulted in a rescue of physical and behavioral FXS phenotypes (Belagodu et al., 2017).Chapter 4 explored and characterized ultrasonic vocalization (USV) abnormalities in FXS mice to find more human relevant behavioral metrics to assess potential therapeutic interventions (Belagodu et al., 2016).Utilizing these studies, Chapter 5 assessed the extent to which blocking VEGF-A can rescue many FXS behavioral abnormalities, such as USV production profiles and behavioral measures of locomotion, anxiety, and stereotypy.Finally, to determine which of the VEGF Receptors are driving the beneficial effects of blocking VEGF-A, Chapter 6 utilized VEGF Receptor specific blockers to assess similar molecular and behavioral properties examined following blocking of VEGF-A.Overall these studies will help to provide further insight into which of the downstream components of the mGluR pathway are playing a role in FXS.In particular these studies will establish which of the VEGF Family and Receptors are driving FXS abnormalities and thus may serve as a viable target for future FXS therapeutics.