Elucidating the Role of Smad4 in Arteriovenous Malformations Associated With HHT
Abstract
Overview of the proposed research project: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by abnormal blood vessel formation. These vascular malformations often involve small blood vessels (Telangiectasias) located in the skin and lining of the nose. In addition, connections between larger arteries and veins can occur, called arteriovenous malformations (AVMs). Typically, blood does not flow directly between arteries and veins, but rather through small intervening vessels called capillaries. Capillaries provide a conduit for the passage of blood between arteries and veins by off-setting the differences in blood pressures (high in arteries, low in veins). In AVMs, arteries and veins directly connect, often leading to fragile sites that rupture and bleed due to the rapid changes in blood pressure. Depending on where hemorrhaging occurs, AVMs can result in minor to chronic nosebleeds, and more serious conditions such as aneurysms in the brain and even death. HHT affects males and females from all racial and ethnic groups and is found in approximately 1 in every 5000 people. In actuality, this number may be an underestimation, as HHT can be difficult to diagnose. Moreover, genetically normal individuals can present with idiopathic (spontaneous) AVMs, at a higher rate of incidence than AVMs associated with HHT. The causes of HHT have been linked to a particular genetic pathway called the transforming growth factor-beta (TGFbeta) signaling pathway. Nearly 80% of patients affected with HHT are linked to mutations in two genes in this pathway, Endoglin (Eng) and Activin receptor-like kinase 1 (Acvrl1), while 2% of HHT patients have been reported to have defects in a third member of this pathway called Smad-related protein 4 (Smad4). To date, the major focus on HHT research has been directed towards the roles of Eng and Acvrl1. This is in part due to the low occurrence of HHT patients with mutations in the Smad4 gene (2%). However, we point out that that this low incidence is due to Smad4 having important functions in other tissues during development, while Eng and Acvrl1 predominately function in blood vessels. For this reason, mutations in Smad4 are more detrimental and therefore fewer people are born with defects in the Smad4 gene. Interestingly, both Eng and Acvrl1 function through Smad4, which in turns controls whether certain genes are turned on or off. Given this relationship, it is surprising that the Smad4 part of the pathway hasn’t garnered any attention. For this reason, we have developed a novel mouse model whereby we abolish the Smad4 gene in blood vessels and readily observe large AVMs in the retina of the eye. Having this model allows us to better understand Smad4’s role in formation of AVMs, which is completely unknown and will have an immediate impact on the scientific community studying AVMs and HHT. Furthermore, by the nature of how Smad4 works (turning other genes off and on), we can address major, fundamental questions that remain virtually unanswered in the field: What are the molecular and cellular events that cause the formation of AVMs and what other genes are involved in this process? This second part is particularly interesting because ~15% of HHT patients have no genetic defects in Eng, Acvrl1, or Smad4, and limited data linking alternative genes to AVMs/HHT has been published. Therefore, it is highly likely that other genes controlled by Smad4 play prominent roles in the development of AVMs/HHT. To this end, we have begun to analyze the genome (all genes) in Smad4 associated AVMs in hopes of uncovering new genes involved in their formation. Through these preliminary experiments, we have identified several strong candidates with previously unknown roles in AVMs/HHT. We propose to deduce their role(s) in the formation and possible regression of AVMs/HHT, as well as identify more potential AVM causing genes. These new findings will have lasting imp
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710349
Entities
People
- Stryder M Meadows
Organizations
- Tulane University of Louisiana
- United States Army