Connexins as Potential Biomarkers and Therapeutic Targets for Vascular Malformation
Abstract
Blood vessels are highly organized networks of arteries, capillaries, and veins. Proper blood vessel development requires coordinated communication between many different cell types that make up the blood vessel wall. In patients with mutations that disrupt signaling mechanisms that regulate blood vessel cell communication – as in the genetic disease Hereditary Hemorrhagic Telangiectasia (HHT) – this can lead to the formation of abnormal, disorganized blood vessels (termed vascular malformations) that are prone to sudden and serious bleeding. Vascular malformations are a Congressionally directed Topic Area for the Peer Reviewed Medical Research Program for the 2020 Fiscal Year. HHT affects 1 in 5,000 live births. Because it can vary in its clinical presentation, HHT can be difficult to diagnose. Symptoms often begin in childhood and progress in severity, but patients typically do not receive a definitive HHT diagnosis until >40 years of age. Thus, some active military personnel may unknowingly have HHT and vascular malformations, and so are at risk for spontaneous, debilitating bleeding episodes – particularly dangerous if they occur in the field. Furthermore, most military personnel are male; men with HHT have higher frequency of certain types of vascular malformations, including some that can lead to potentially fatal complications. Yet, early screening and treatment options for HHT are mostly unavailable. Many HHT patients have a mutation that affect a protein called Alk1, but how this leads to vascular malformation is still unclear. Preliminary data show that Alk1 in turn regulates expression of a family of proteins called connexins (Cx). Cxs form channels – termed gap junctions – that support cell-to-cell communication of signals that affect cell proliferation and migration, which are processes essential for healthy blood vessel development. Thus, our central hypothesis is that in healthy blood vessels, Alk1 regulates the balance of connexins to stabilize blood vessels, and that loss of this regulation in HHT contributes to vascular malformation. We will test this hypothesis with the following aims: Specific Aim 1: Determine how abnormal Cx expression in the vessel wall contributes to vascular malformation. Using a recently developed HHT disease model comprised of engineered human blood vessels, we will: 1A) map how Cx expression changes as vascular malformations develop; 1B) engineer blood vessel cells that abnormally express Cx proteins and determine how this affects development of vascular malformations; and 1C) measure how abnormal Cx expression affects gap junction channel function in blood vessel cells. The outcomes of this aim will help us to understand how Cxs prevent vascular malformation in healthy blood vessels, and how this goes wrong in HHT. Specific Aim 2: Determine how Cx expression profile may predict risk and severity of vascular malformation. We will secure donor tissue and blood samples from healthy and HHT patients. We will: 2A) use these to assess how Cx expression is changed in HHT patient populations; and 2B) determine whether subtle variations in Cx genes might impact the severity of HHT symptoms. Taken together, we expect outcomes of this aim to identify Cxs as a new biomarker candidate that may be able to predict the risk and severity of vascular malformations in HHT. Specific Aim 3: Determine whether manipulation of Cx expression can resolve or prevent vascular malformations. In a novel HHT disease model, we will: 3A) determine if enforcing normal Cx expression in blood vessel cells can prevent or repair vascular malformation even in the absence of normal Alk1 expression; 3B) determine if drugs that target Cxs can also prevent or repair vascular malformations; and 3C) screen for other cell signaling pathways that are regulated by Cxs. We expect the outcome of these studies to determine how Cxs might be leveraged to develop new HHT therapies, and to also identify additional cand
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110108
Entities
People
- Jennifer Fang
Organizations
- United States Army
- University of California, Irvine