Abstract 2385 The role of the ALK1 protein in vascular disease and potential targetability in Crohn's disease

The ACVRL1 gene is highly expressed in endothelial cells and encodes the transmembrane protein activin receptor-like kinase 1 (ALK1), which is a type I cell-surface receptor serine/threonine kinase for the transforming growth factor-β (TGF-β) superfamily of ligands BMP9/GDF2 and BMP10. ALK1 comprises of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular kinase domain. Upon ligand binding, this receptor forms complexes with other TGF-β receptors, primarily BMP9 to activate intracellular downstream signaling pathways. The Smad pathway functions to regulate gene expression through transmitting nucleus signals from the TGFβ receptors. Signaling is transmitted by a cytoplasmic kinase domain of ALK1 by phosphorylating receptor-regulated Smad proteins (R-Smad proteins). Activated R-Smad proteins and the common-Smad (co-Smad) form a complex to regulate transcription of target genes together with cofactors. This pathway is essential for angiogenesis and vasculogenesis and a mutation can induce several vascular diseases. The Smad Pathway is also crucial for endothelial cell differentiation and homeostasis, which plays roles in Crohn's Disease. Differing mutations in the ACVRL1 gene can result in increased or decreased kinase activity as well as impaired ligand binding, disrupting of TGF-β signaling, and in some cases induce a rare genetic disorder known as Hereditary Hemorrhagic Telangiectasia (HHT). HHT is an inherited disorder characterized by abnormally formed blood vessels. TGF-β can act as both a tumor suppressor and a tumor promoter, and mutations or dysregulation of components in its pathway can lead to several types of cancer. In Crohn's disease patients, scientists were able to determine an increased risk of endoscopic relapse based on ALK1 levels. Additionally, activation of ALK1 has been shown to enhance colonic intestinal epithelial barrier integrity and function ex vivo in these studies. The Walton High School SMART team, with support from 3D molecular designs, has modeled ALK1 receptors to support testing of the ALK1 protein to develop potential therapies and interventions for Crohn's disease, HHT, and several cancers.