Pathogenesis of Vascular Malformations in Hereditary Hemorrhagic Telangiectasia: From Disease Mechanism to New Therapies
Abstract
This Focused Program Award application titled, “Pathogenesis of Vascular Malformations in Hereditary Hemorrhagic Telangiectasia: From Disease Mechanisms to New Therapies,” is submitted in response to the request for applications for the Fiscal Year 2016 Peer Reviewed Medical Research Program topic area of “Vascular Malformations.” Vascular malformations (VMs) are abnormal clusters of blood vessels that can develop in any part of the body. The medical consequences of a VM can vary, but one of the most significant dangers is its propensity to bleed. Our study will investigate the prototypical VM found in the inherited disease, Hereditary Hemorrhagic Telangiectasia (HHT). HHT is inherited as an autosomal dominant condition, which means that children of an affected parent have a 50% chance of inheriting the mutant gene and developing the disease. The VMs found in HHT range from small lesions on the skin, lips, mouth, and in the intestines, called telangiectasias, to large VMs in internal organs (liver, lung, brain), called arteriovenous malformations. In addition to their propensity to bleed, the large arteriovenous malformations pose additional medical problems including stroke, seizure, and internal bleeding, all of which can be life-threatening. Our choice to study VMs that occur in an inherited form of VMs is deliberate. Advances in our understanding of more common diseases can often be made by the study of less common, inherited diseases, for which information is available at the genetic level. Indeed, the mutated genes responsible for these genetic diseases can provide us with the first clue to the underlying basis of the disease and, by analogy, the other forms of the disease. During the past two decades, a member of our research team identified three genes that when mutated cause HHT in the vast majority of the affected families. These genetic discoveries have led to a better understanding of HHT and, importantly, the development of animal and cell models of the disease, without which future experiments for new treatments would be severely limited. Currently, the two animal models of HHT that most faithfully replicate the human disease have been developed in zebrafish (a popular aquarium fish) and the laboratory mouse. Importantly, the two scientists who developed these animal models of HHT are also members of our research team. Despite these tremendous scientific advances, we still do not fully understand what causes the VMs to develop in HHT, and, due to this lack of information, there is no highly effective therapy. In one project, we will test the idea that the VMs are initiated by a second mutation that occurs in the cells lining the blood vessel. The results of this study have implications for how we might go about treating the VMs in HHT. In another project using the mouse model of HHT, we will determine whether we can increase the dose of the mutant gene, or bypass altogether the genetic defect, in order to repair the defect in the vessels. Another project will use patient-derived blood cells to identify existing drugs that may be effective at increasing the function of one of the defective HHT genes. Another project seeks to engineer a new drug by developing a mimic of one of the known components of the biochemical pathway that is defective in HHT. Each project takes advantage of the unique strengths of the project leader’s demonstrated expertise. Significantly, by studying VM formation across multiple models and experimental approaches, we have a better chance to discover a new therapy for VMs. A final project anchors the entire research program. We will attempt to control bleeding in HHT patients by treating them with one of two different drugs commonly prescribed for different purposes. We hope to learn whether drug “repurposing” of one of these commonly prescribed drugs will reduce VM-associated bleeding. But equally important, these studies also set the foundation for any futur
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710429
Entities
People
- Suk Oh
Organizations
- Dignity Health
- United States Army