Genetics of cerebrovascular anomalies

The genetic defects in several familial or inherited types of stroke syndromes are known; much less well understood are the genetic defects in "sporadic" stroke syndromes. In collaboration with the UCSF Cardiovascular Research Institute and the Department of Genetics at Duke University, these studies are designed to define the interaction of subtle genetic alterations in key signaling pathways that are necessary for normal development and maintenance of the vascular endothelium. If these systems are not operating correctly, defects such as structural flaws in the blood vessel or a predisposition to clot formation may result.

Brain Vascular Malformation Consortium

Rare Diseases Clinical Research Network (RDCRN), an initiative of ORDR, NCATS: Brain Vascular Malformation Consortium
This project is funded through collaboration between NCATS and NINDS to explore the natural history, epidemiology, diagnosis, and treatment of several rare vascular diseases of the brain. See the following presentation. In collaboration with patient advocacy groups (PAGs), we are actively recruiting patients with familial cerebral cavernous malformations (CCM), Sturge-Weber Syndrome (SWS), and hereditary hemorrhagic telangiectasia with and without brain arteriovenous malformations (BAVM).

Epidemiology and clinical course of brain arteriovenous malformations (BAVM)

BAVMs are a rare but treatable cause of stroke from bleeding into the brain. These studies seek to define what the risks of neurologic damage are from both the natural history of the disease as well as from treatment of the disease. By knowing the balance between natural history and treatment risks in different subgroups of patients, more rational care can be offered to patients. Use of novel clinical trial methodologies and statistical modeling are used for this work. Parts of these studies are undertaken in conjunction with Kaiser-Permanente Northern California to examine aspects of natural history in a population-based cohort.

Hemorrhage-Free Survival after BAVM Presentation

Endothelial biology of brain cerebrovascular malformations

By examining surgical specimens with the tools of molecular biology, the pathways associated with the development of human vascular malformations can be studied. Examples of these malformations include BAVMs, cavernous malformations, dural arteriovenous fistulas, and aneurysms. By use of cell culture systems and the development of small animal models, mechanistic studies can be undertaken to unravel the missteps in development or maturation which result in the human disease. From these studies, insights into better treatment strategies can be undertaken. A key system of interest is the Tie-2 / Angiopoietin signaling pathway.

Cerebrovascular malformation modeling, mechanistic study and new therapy development

Modeling, exploring the pathogenesis and developing new therapies for arteriovenous malformation (AVM) are the major focuses of the basic research team. Through manipulation of relative genes, and the levels of various angiogenic factors, we have successfully built several brain arteriovenous malformation (AVM) models. These models also have AVM in other organs. They are powerful tools for dissecting AVM pathogenesis and test innovative therapeutic strategies. The figures show an AVM lesion in the brain in one of our models.

Impact of peripheral and brain injuries

We found that long-bone fracture upregulates innate immune response systemically and locally in the brain, which causes exaggerated neuronal damage and behavior deficits. We are trying to understand how peripheral injury influences stroke recovery. We are also testing new strategies to modulate innate immune response to improve the outcomes in stroke patients with advanced age or with peripheral injury.

Computational modeling of the cerebral circulation

By the development of computational models, it is often possible to take incomplete sets of experimental data and generate likely hypotheses to further test. Further, theoretical modeling of BAVM rupture risk can be used to improve selection of variables to develop for use in risk stratification purposes in clinical trials. A long-term goal of this line of inquiry is to eventually develop "patient-specific" physiologic models that can be used in conjunction with modern anatomic imaging for treatment planning and outcome assessment.

In collaboration with scientists from the Vascular Imaging Research Center, we are studying the effect of abnormal flow profiles that are present in cerebral aneurysms and arteriovenous malformations using magnetic resonance imaging and computational fluid dynamic modeling.