Dynamic Cell-Matrix Interactions Dictate Thoracic Aortopathy

PROJECT SUMMARY – CORE A: ADMINISTRATIVE Thoracic aortopathy – aneurysms, dissection, and rupture – is increasingly responsible for significant morbidity and mortality in Americans of all ages, independent of sex. Despite many seminal discoveries since 1991, when the genetic basis of Marfan syndrome was uncovered, much remains unknown and therapeutic strategies remain limited. We submit that significant new understanding and new actionable therapeutic targets will stem from coordinated and comprehensive testing of the compelling overall hypothesis that aberrant cell-extracellular matrix interactions that compromise tissue homeostasis are primary drivers of thoracic aortic disease. Here, we bring together 5 leading laboratories to address 5 critical contributors to compromised homeostasis, or its treatment, in the thoracic aorta; importantly, these labs have made significant prior contributions to understanding thoracic aortopathy and have a track-record of successful collaborations as evidenced by papers and grants. Core A: Administrative will nonetheless work to seamlessly coordinate all activities – those with the NIH, those across institutions (Yale and UT-Health), those amongst the 5 laboratories, those with the External and Internal Advisory Boards, those with the trainees, and those with the PPG-specific and university-sponsored cores. We propose, in this Core, what we feel will be a highly effective administrative structure (with a consensus-driven Executive Committee providing oversight) and a similarly effective Yearly Calendar with associated monthly, semi-annual, and annual activities to promote interactions, emphasizing both the science and opportunities for training while promoting diversity, equity, inclusion, and belonging amongst our overall team. Importantly, Core A will ensure the use of consistent and authenticated methods to collect, analyze, synthesize, and share complementary data sets, addressing 5 of the key factors that contribute to thoracic aortopathy. Core A will also ensure timely presentation and publication of results and will ensure appropriate documentation, reporting, data management, and resource sharing, including data availability. Finally, Core A will ensure compliance with all federal and state requirements. We expect this Administrative core to ensure that our highly integrated approach will yield unique insights into thoracic aortopathy and its potential treatment.