Assessing re-emerging angiogenic properties associated with arteriovenous malformation related to HHT
Description
My Honors Thesis is focused on the human genetic disorder called Hereditary Hemorrhagic Telangiectasia (HHT). This disease affects the vascular system and is present in approximately 1 in 5000 people. The most severe symptom in these patients is the formation of arteriovenous malformations (AVMs). AVMs result from arteries and veins improperly connecting. The goal of this project is to better understand the molecular and genetic causes of AVMs, which are currently unknown. The Meadows lab has developed a mouse model that forms AVMs in the retina when knocking out the gene Smad4, which is known to be a transcriptional regulator in the TGFï¢ pathway. By knocking out the transcriptional regulator Smad4, the Meadows lab has identified potential downstream molecules responsible for the development of AVMs. Three of these genes, Angiopoietin 2 (Ang2), Apelin (Apln), and Endothelial Cell Specific Molecule 1 (Esm1), are hypothesized to be inhibited by Smad4, since when Smad4 is knocked out, Ang2, Apln, and Esm1 are being found to be overexpressed. Interestingly, these genes are implicated in the active process of angiogenesis, which is thought to be upregulated and responsible for AVM formation. Using this mouse model and molecular biology lab techniques, I have measured the effect of the loss of Smad4 as it results in the overproduction of Ang2, Apln, and ESM1 at the transcriptional level and tested whether Smad4 regulates the transcription of these genes. These findings confirm that Smad4 is directly involved in the repression of these genes, further indicating their repression is important to inhibiting AVM development.