This proposal will continue the longstanding focus of this research program in 3 related areas: 1) the molecular pathogenesis of disorders in von Willebrand factor (VWF) function, 2) the genetic factors that modify the manifestations of other inherited bleeding and blood clotting diseases, and 3) regulation of protein transport from the ER to the Golgi apparatus and its role in the pathogenesis of blood diseases. VWF is a key component of the blood coagulation system whose deficiency resulting in the most common inherited bleeding disorder in humans, von Willebrand disease (VWD). Elevated levels of VWF are a major risk factor for thrombosis, with loss of VWF processing by ADAMTS13 resulting in thrombotic thrombocytopenic purpura (TTP). This project will exploit recent transformative advances in genomic technology to uncover novel pathways contributing to the control of VWF and ADAMTS13 function and lay the foundation for a ?precision medicine? approach to these disorders. A novel VWF regulatory gene previously mapped to human chromosome 2 will be identified through genomic sequence analysis in an additional large cohort of human subjects and its function explored through modeling by ?genome editing? in laboratory mice. Similar tools will be used to characterize a novel modifier gene for TTP susceptibility mapped to mouse chromosome 5. We will also assemble a comprehensive dataset for the functional impact of all possible single amino acid substitutions within the VWF A1 and A2 domains to provide a complete inventory of potential human mutations causing type 2A, 2M and 2B VWD. These data will address the increasingly important clinical problem of ?variant of uncertain significance?, a key challenge for the entire field of human genetics, and should lay the foundation for eventual diagnosis and subclassification of VWD on the basis of DNA sequence alone, enabling true ?precision medicine?, and serving as a useful paradigm for other genetic diseases. This program will also focus on identifying novel genes that contribute to venous thromboembolic (VTE) disease susceptibility, both by direct genomic sequence analysis in human VTE patients, as well as a broad whole genome mutagenesis screen for thrombosis suppressor genes in laboratory mice. Finally, in a ?bedside? to ?bench? translation, the lab has broadened its studies of the rare inherited bleeding disorder, combined deficiency of factors V and VIII, to explore the basic function of cellular transport pathways leading to unexpected insights into the molecular pathogenesis of congenital dyserythropoietic anemia II and the regulation of plasma cholesterol levels. These findings are now circling back from the ?bench? to the ?bedside?, with the potential to provide improved diagnosis and therapy for related diseases. Taken together, this research program will apply cutting-edge genetic and genomic technologies to identify critical genes modifying the risk and severity for a number of blood and heart diseases, as well as yielding information about fundamental biologic processes that could lay the ground work for future novel approaches to the diagnosis and treatment of these disorders.
The studies proposed in this application will advance understanding of genes that contribute to the severity of bleeding or blood clotting in a number of important human diseases, including von Willebrand disease, thrombotic thrombocytopenia, and venous thrombosis. These findings should lead to improved diagnosis for both inherited bleeding and blood clotting diseases and facilitate more tailored selection of therapy in individual patients. These studies may also lay the groundwork for the development of new therapies in the future to treat both common bleeding and blood clotting diseases.
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