Identification of novel treatment targets through improved pathomechanistic insight in IPO8 deficient aortopathy.

Thoracic aortic aneurysm (TAA) is an abnormal widening of the thoracic aorta caused by blood vessel wall weakness. TAAs entail a high risk for aortic rupture or dissection, commonly leading to sudden death. To date, genetic defects in >35 genes have been linked with TAA, providing a molecular cause for about 30% of patients. Their identification and functional characterization have been key in acquiring our current pathomechanistic aortopathy knowledge. Yet, the genetic and mechanistic picture for TAA is far from complete, hampering identification of predictive markers for aneurysm formation and development of therapies capable of stopping or reversing aneurysm formation. In search for novel TAA genes, our research group most recently identified recessive truncating IPO8 mutations as a novel cause of syndromic TAA. This project builds on this exciting finding, remarkable Ipo8-/- mouse background differences and the availability of IPO8 mutant iPSCs and isogenic controls. More specifically, we aim to significantly improve our current pathomechanistic insight in TAA caused by IPO8 deficiency based on 1) transcriptomics to unravel the involved biological pathways; and 2) identification of proteins and miRNAs with an abnormal cytosol/nucleus distribution upon IPO8 depletion. In the long term, this project's anticipated results will identify new targets for drug therapies, improving TAA patient management.

Keywords:THORACIC AORTIC ANEURYSM

Disciplines:Genetics, Intracellular compartments and transport, Stem cell biology, Vascular diseases, Transcription and translation