Defining the Role of the RAS Pathway in Brain Arteriovenous Malformations
Abstract
A brain arteriovenous malformation (BAVM) is a tangle of large, abnormal blood vessels within the brain. Normally, blood flows from arteries to veins via a network of tiny blood vessels called capillaries, which enables oxygen and nutrient absorption into tissues and also helps to control blood flow and pressure. In a BAVM, there is no capillary network between an artery and a vein. Without this intervening capillary network, blood flows from the arteries to the veins at a very high flow rate and under high pressure. The resulting high blood pressure in veins can place a patient at substantial risk of blood vessel rupture and hemorrhage (which is a type of stroke). The consequences of these hemorrhages can be devastating: ranging from severe disability to death. Treatment of a BAVM with brain surgery or radiation is highly invasive, poses significant risk to the patient, and is incredibly costly. Additionally, this hemorrhagic stroke may occur before the BAVM is treated or even during surgical treatment. There are currently no drugs available to treat this disorder. These malformations are a significant burden, both in terms of patient quality of life and cost of treatment. The genetic cause(s) of BAVMs are not known. Our objective is to identify the specific genetic changes that occur within a BAVM and to determine how they contribute to these vascular malformations. By identifying the genetic cause(s) of BAVMs, we hope to identify the first drugs to non-invasively treat BAVM patients. BAVMs are difficult to study since they are relatively rare (prevalence of ~0.2%). However, since the Toronto Western Hospital has a large and well-established BAVM clinic, we have managed to build a unique and extensive collection of BAVM tissue, so that we are now in a very privileged position to study this disorder. The cause of BAVMs is not known; however, it is unlikely that inherited mutations are directly responsible for BAVM occurrence. We are therefore searching for “somatic” DNA mutations within BAVMs. These are mutations that happen spontaneously in the affected tissue and are not familial traits (i.e., inherited from the patient’s parents). Our initial experiments have uncovered a mutation in a gene known as KRAS. This mutation occurs within the cells lining the blood vessel malformation, known as endothelial cells. We hypothesize that this somatic DNA mutation in the KRAS gene may be the cause of BAVMs. Somatic mutations in other genes have been observed in other blood vessel abnormalities, but never in BAVMs. If we are able to confirm our preliminary results and show definitively the role of KRAS in BAVM, this will be a major breakthrough in this field of research. Since the KRAS mutation is found in the endothelial cells within a BAVM, we will test the consequences of mutating KRAS in the endothelial cells of vertebrate animals whose physiology and genetics mirror our own (i.e., mice and zebrafish). These models will allow us to determine what happens to the structure of blood vessels when KRAS becomes mutated in endothelial cells. By modeling the disease, we can begin to understand how altered KRAS function leads to BAVM formation. Since mutant KRAS protein is known to continually send growth and migration signals to cells, we will determine what these signals are and will search for drugs that can inhibit these responses. We will then determine whether these drugs are able to halt or reverse the pathology of BAVMs in animal models. In addition to defining the mechanism through which KRAS leads to BAVMs, we will search for additional somatic mutations involved in BAVMs. Additional mutations may be found within KRAS, or in other genes that affect KRAS function, shedding more light on the mechanisms of BAVM disease progression. Accordingly, we will sequence the DNA from patient’s BAVMs and compare that to the DNA sequence from blood of the same patient (to identify non-germline, somatic mutation
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810350
Entities
People
- Joshua D Wythe
Organizations
- Baylor College of Medicine
- United States Army