Wednesday, January 15, 2025
1/15/2025
Abstract The Ehlers Danlos Syndromes encompass a group of heritable connective tissue disorders with a complex phenotype affecting multiple body systems. Among these, the hypermobile subtype of EDS (hEDS), is the most common type of EDS affecting 1 in 500 individuals. The disease phenotype is characterized by hypermobile joints that lead to musculoskeletal defects, skin manifestations, tissue fragility, and multiple comorbidities. The healthcare burden associated with hEDS is substantial, with patients often requiring care from a variety of medical specialists, frequent surgeries and hospitalizations, management of debilitating chronic pain, and consistent physical and occupational therapy. Despite well-documented inheritance, the genetic causes of hEDS remain unclear, and diagnosis relies on clinical criteria, resulting in an average 14-year delay in diagnosis. There are currently no direct treatment options for hEDS other than symptom management. Recent findings from our group have highlighted the crucial role of a gene family of trypsin-like serine proteases in hEDS. This proposal will build on these discoveries by exploring the molecular, cellular, and additional genetic mechanisms that contribute to hEDS pathogenesis and connective tissue homeostasis. We will explore how proteins encoded by hEDS genes regulate collagen fibrillogenesis (Aim 1), investigate their contribution of mast cells to altered extracellular matrix (Aim 2), and perform genome wide association studies (GWAS) to reveal common variants associated with hEDS and connective tissue biology (Aim 3). By employing our unique and novel mouse models and leveraging our extensive clinical genetic registry, we aim to gain novel insights into the pathogenesis of hEDS and its related comorbidities. From these discoveries, we aim to accelerate the development of targeted therapies for hEDS, create more accurate molecular diagnostic tools and ultimately alleviate the burden on patients and the healthcare system.
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