Developing novel, functional biomarkers fo vEDS

Project Leaders: Elizabeth Doherty

Undergraduate Researchers: Emily Warren, Grace Kohn

Authored by: Elizabeth Doherty

Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder that is caused by autosomal dominant mutations in the COL3A1 gene, resulting in mutated procollagen-III and subsequent loss of collagen III in the ECM of patient’s hollow organ tissues. This has consequences for the mechanical integrity of these hollow organs, in particular blood vessels, and presents with sudden rupture or aneurysm of patient vasculature with limited intervention options. Our lab is interested in investigating how differences in mechanical failure are attributes of the disease at a cellular level and how they may impact mechanotransduction in vascular cells and vascular cell phenotype as biomarkers for disease.

We have used in vitro methods to generate cell-derived matrix from patient derived cells to characterize the mechanical, compositional, and structural properties to find key differences between the genotypic variants of vEDS cell-derived matrix and fibroblasts. We aim to further probe the effects of these genotypic differences on vascular endothelial cells to determine if there are pathological consequences of this mutation on the endothelium and thus further impacts on vascular integrity.

Key collaborators:

Anthony Hickey, PhD - Director of UNC Catalyst for Rare Disease, Eshleman School of Pharmacy, UNC

Matthew Kutys, PhD - Assistant Professor of Cell and Tissue Biology, UCSF

Hadi Nia, PhD - Assistant Professor of Biomedical Engineering, Boston University

Key resources:

Chapel Hill Analytical and Nanofabrication Laboratory

Funding:

University of Pennsylvania Orphan Disease Center in partnership with the Lymphangiomatosis & Gorham's Disease Alliance and the Lymphatic Malformation Institute (co-PIs: Polacheck & Blatt)

NIH Grant T32HL697698 (to Doherty).

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We are developing novel approaches for growing healthy and diseased extracellular matrix in vitro to better understand how genetic mutations harbored in patients with vEDS contribute to the increased risk of aneurysm. 

Engineered vascular malformations

Project Leaders: Dr. Wen Yih Aw, Crescentia Cho, HIRING GRADUATE STUDENTS

Undergraduate Researchers: Anne Hope Cooper

Vascular and lymphatic malformations are associated with considerable morbidity, including mass effects which depend on location, life-long risk of pain, infection, pulmonary emboli, and myriad psychosocial issues. Treatment is rarely curative and has relied on surgery, sclerotherapy, and a limited repertoire of drugs. To better understand how certain genetic mutations, particularly those in the PIK3CA gene, result in malformed vasculature, we have developed engineered microvascular models within microfluidic devices. The low volumes and marginal cost of these platforms allows not only for mechanistic studies, but also for screening experiments to test efficacy of interventional compounds. In collaboration with the UNC Vascular Anomalies clinic, we are working to test whether antiangiogenic drugs developed to treat solid tumors are effective at limiting the growth of vascular lesions in patients with malformations. 

Key collaborators:

Julie Blatt, MD - Professor, UNC School of Medicine, Pediatric Hematology-Oncology

Boyce Griffith, PhD - Associate Professor of Mathematics, UNC.

Key resources:

Chapel Hill Analytical and Nanofabrication Laboratory

UNC Vascular Anomalies Clinic

Funding:

University of Pennsylvania Orphan Disease Center in partnership with the Lymphangiomatosis & Gorham's Disease Alliance and the Lymphatic Malformation Institute (co-PIs: Polacheck & Blatt)

NIH Grant 1R01 CA25845-01 (PI: Pecot)

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We are developing microfluidic approaches for recapitulating vasculogenesis in vitro. By studying the resulting vascular networks formed with healthy cells vs. those formed from cells harboring mutations associated with vascular malformations, we can