RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in Notch4-Induced Mouse Model
Abstract
This project addresses the Peer Reviewed Medical Research Program Topic Area of Vascular Malformations. Rationale: A healthy vascular system is critical for proper blood circulation. Blood flows from the heart through arteries to capillaries, where nutrients, oxygen, and waste are exchanged with the tissue, and returns to the heart through veins. Arteriovenous malformations (AVMs) are severe vascular malformations in which arteries carry blood directly to veins through enlarged vessels, known as AV shunts, bypassing capillaries and thus failing to deliver necessary nutrients to tissues. These AV shunts easily rupture, leading to hemorrhage. AVMs can occur anywhere in the body, but brain AVM (BAVM) is the most dangerous form of the disease, potentially leading to stroke. BAVM often occurs in young people and accounts for 1%-2% of all strokes and for 50% of hemorrhagic strokes in children. Current treatment options are limited to surgeries and radiotherapies to remove malformed vessels, both of which are highly risky and possible only in some BAVM patients. A Randomized trial of Unruptured Brain AVMs (ARUBA) was recently suspended as some interventions caused more harm than no treatment at all. The health risk of BAVM is higher for military personnel than for the civilian population. The disease is most commonly seen in men between the ages of 20-40, who are well represented in the military. In addition, AVMs are often exacerbated by traumatic injury and tend to rupture without prior warning, making BAVMs and the associated strokes particularly dangerous for active Service members. Furthermore, complex, emergency neurosurgical treatments are often unavailable for deployed military personnel. A deeper understanding of the molecular basis of BAVM would inspire new discoveries in diagnostic tools, prevention strategies, and pharmacological treatments, improving prognosis and care for patients in both military and civilian populations. Our central hypothesis in this study is that intermediary proteins in the signaling pathway governed by the cell surface protein Notch may serve as new therapeutic targets for BAVM treatment. Through extensive past research on BAVMs, we have reported that the Notch pathway is hyperactive in BAVM patients. Introducing a constantly active mutant of Notch, called Notch4*, in mice results in BAVMs in 100% of animals. Correcting this experimental mutation leads to healing of fully formed BAVMs in mice, demonstrating that BAVMs can be treated by a molecular-level intervention. Our pilot studies suggest two possible target molecules and one potential drug therapy in the Notch pathway, each warranting further investigation. Objective: We propose testing these three treatment strategies using our preclinical animal model. In the first two lines of investigation, we plan to inhibit two proteins in the Notch signaling pathway, Rbpj and ephrin-B2. Using our lab s extensive experience in mouse genetics, we will inhibit each protein either in all vessels or specifically in arteries and then specifically in veins. This strategy will help to uncover the best site for targeting these molecules to maximize efficacy and minimize side effects. Next-generation drug delivery strategies will enable the effect of drugs to be restricted to specific segments of vessels. As a third possible strategy, we also plan to test a drug that has been tested for Alzheimer s disease therapy in humans, DAPT21, which inhibits Notch activity. Further, we plan to use state-of-the-art two-photon imaging techniques from our Partnering PI s laboratory to visualize disease processes in living animals in real time and provide the first clues on exactly how BAVMs regress after these three interventions. Short-Term Impact: Our study will show the effectiveness of these three treatment strategies. We will improve understanding of the Notch signaling pathway in BAVM prevention and treatment, provide a refined pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610665
Entities
People
- Rong Wang
Organizations
- United States Army
- University of California, San Francisco