Dynamic Cell-Matrix Interactions Dictate Thoracic Aortopathy

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY – OVERALL PROGRAM Thoracic aortopathy – aneurysms, dissection, and rupture – is increasingly responsible for significant morbidity and mortality. Despite many seminal discoveries since 1991, when the genetic basis of Marfan syndrome was uncovered, improvement in clinical care has largely remained limited to better identification of patients with pathogenic variants who need monitoring of aortic diameter until intervention coupled with improvements in surgical methods and devices. There is, therefore, a pressing need for improved understanding leading to improved medical treatments. In this PPG, we will test the compelling overall hypothesis that aberrant vascular cell-extracellular matrix (ECM) interactions that compromise tissue homeostasis are primary drivers of thoracic aortic disease. That is, dysfunctional mechano-sensing and mechano-regulation of medial ECM by smooth muscle cells results in a progressive deterioration of the biomechanical integrity of this critical layer of the thoracic aorta, leading to progressive dilatation with possible dissection and rupture. Although such aortopathy often arises due to a predisposing monogenic variant, secondary changes in cell signaling and gene expression can represent either protective compensations or pathological consequences. In the absence of gene editing to correct the predisposing variant, there is a need to distinguish and then preserve / promote compensatory gene products while preventing pathological ones. In other words, there is a need (i) to identify and promote any homeostatic processes that contribute to the remarkable resiliency of the aorta against incessant hemodynamic stresses and that may similarly help to attenuate disease progression and (ii) to prevent secondary processes that exacerbate disease progression, particularly in the presence of risk factors such as hypertension. This PPG uses 3 Projects to elucidate roles of the 3 complementary nodes along the dysfunctional mechano- biological axis and 2 Projects both to quantify effects of a primary risk factor (hypertension) and to provide high- throughput integration and testing (experimental and computational) of findings across all main disease models in order to better understand the underlying molecular, cellular, and biomechanical mechanisms of aortopathy and to identify new actionable targets for treatment. Although highly complementary given our unifying central hypothesis, each individual Project represents distinct, scientifically innovative, and significant research; two Cores, one Administrative and one Scientific, will ensure close communication, collaboration, and consistent data collection and analysis. The 5 Project leads have an established track record of highly productive collaborations and contributions to vascular biology and thoracic aortopathy, and they have developed the foundations for this work over a period of years, leading to intense activity over the past year to define this PPG.