Optimization and Translational Validation of a Novel Mouse Surgical Model of Moyamoya Syndrome

Moyamoya is a chronic cerebrovascular condition characterized by the progressive stenosis of the intracranial internal carotid artery (ICA) and its major branches. Reduced blood flow in these major arteries leads to ischemia and compensatory development of new blood vessels throughout the brain. Those new collaterals are abnormal, and can rupture to cause intracranial hemorrhage. Affected patients often suffer from headache, transient ischemic attacks (TIAs), ischemic stroke, seizures, and hemorrhagic stroke, which lead to focal disabilities and progressive cognitive impairment. While the pathophysiology remains elusive, we do know it presents in two forms. The congenital form (moyamoya disease) commonly occurs in the East Asian population and typically affects children under the age of ten. The sporadic form (moyamoya syndrome) usually presents in the Caucasian population, is commonly associated with autoimmune diseases and other comorbidities, and affects adults in their 20-40s. In our Kentucky region, patients typically present with moyamoya syndrome, and the incidence is much higher than reported in other US regions, indicating a great need to understand moyamoya pathogenesis for the development of novel treatment options. The ICA and other cerebral vessels are known to have alterations to the vessel wall structure, including intimal thickening, proliferation of the vascular smooth muscle cells, and fragmented elastic lamina. Interestingly, macrophages and T cells have been found to infiltrate the thickened intima of occlusive vessels and immunomodulatory molecules such as cytokines, growth factors, and endothelial adhesion molecules are elevated in the cerebrospinal fluid (CSF) and blood of moyamoya patients. These vessel pathologies are thought to be responsible for the stenosis, though there is debate as to whether inflammation is a causal factor or if it is a result of the stenosis and ischemia associated with the condition. Indeed, a major research barrier to better understanding the pathogenesis of moyamoya is the lack of a translatable animal model. To address this unmet need, I recently developed an animal surgical method that I hypothesize could potentially model moyamoya syndrome. To validate the translational potential of this moyamoya syndrome model, I propose to evaluate biochemical markers in the blood of moyamoya syndrome patients and correlate the levels to clinical and radiographic scales. Additionally, I will optimize the animal surgical method to correlate with the human demographics and various severity stages. Together, data collected here will provide increased understanding of moyamoya syndrome pathogenesis and a translational model in which to investigate long-awaited novel therapies.