The Steven Chang Lab's Research

The goal of our research efforts is to develop and implement new technologies to improve the diagnosis and treatment of rare neurological conditions. We are focused on finding less invasive ways to diagnose disease and translating our discoveries in the lab to patient care. We are primarily interested in discovering novel, more accurate and less invasive ways to diagnose disease, using our findings to move patient care toward more personalized and effective treatment options, and to bring technology to the bedside. 

Blood vessels bring oxygen- and nutrient containing blood to the entire body; however the vessels of the brain are unique from those of the rest of the body, in that they possess a selective ‘gate’ for what goes in and out of the brain, called the blood-brain-barrier.  The brain is highly reliant on proper blood flow – while only about 2% of the body mass, the brain consumes 20% of the oxygen.  Understanding the process by which blood vessels form, respond to damage, and repair themselves is important for research on:

• Vascular malformations: characterized by overgrowth or dysfunction of the vessels, as seen in arteriovenous malformations, and aneurysms
• Brain tumors: recruit new blood vessel formation to feed the growing tumor
• Stroke:  recovery from which depends in part on new blood vessel growth restoring blood flow to vulnerable areas of brain
   

A crucial research question is how vascular malformations and cancer, despite both involving vascular growth and sharing many signaling pathways, have strikingly different outcomes.

Our researchers are leading the efforts in biomarker discovery, a process that focuses on isolating circulating factors in biofluids (blood, urine), as well as genetic variations that relate to specific characteristics of vascular malformations or tumors in patients.  Biofluids are obtained from patients prior to and following treatment and/or removal of their vascular malformation or tumor.  Differences in biomarkers before and after treatment are also being related to tissue obtained from surgery to obtain more information about these diseases and to design better treatment.  For example, Dr. Steven D. Chang hopes to one day offer his patients a simple blood test that he can use to determine whether a particular patient will benefit from neurosurgery versus radiosurgery.  The ultimate goal is to practice personalized medicine, which Dr. Chang calls “the right treatment, in the right patient, at the right time.”

Our group focuses on rare diseases of the cerebrovasculature, in particular arteriovenous malformations.  Diagnosis of an AVM is challenging and usually occurs only after the patients suffer hemorrhagic stroke, seizures or other issues.  Because the treatment plans are not routine or standard, there is often a significant amount of time before the AVM is resolved, increasing stress for patients and family.  Our goal is to develop more effective ways to both diagnose and treat AVMs.  Our research is highly translational and is based entirely on human samples, facilitated by the Department of Neurosurgery, the SNIP team, and Stanford patients.  We have taken various biochemical, genetic and biological approaches to further advance our understanding of the basic disease mechanisms.

Arteriovenous Malformations (AVMs)

AVMs can be found throughout the brain and are characterized by a tortuous ‘nest’ of arteries and veins, which lack a normal capillary bed.  To understand the mechanisms of this disease, we have focused on the unique protein and RNA expression of AVM tissue.  In our previously published work, we showed that the endothelial cells (EC) that line the blood vessels are not clearly arterial or venous and also express proteins typically associated with the acquisition of a lymphatic EC fate.

Related to this ambiguous EC identity, we now have evidence for a crucial disease process in human brain AVMs called endothelial-to-mesenchymal cell transition (EndMT).  EndMT has recently been described in sporadic and familial Cerebral Cavernous Malformations, a cerebrovascular disease similar to but distinct from AVMs.  In EndMT, ECs shift from normal and mature to proliferative and migratory.  This change can result in ‘leaky’ blood vessels and hemorrhage, and also disrupts the normal cell-to-cell interactions in the brain.  EndMT has been implicated, and studied intensively, in other diseases such as pulmonary fibrosis, cardiac disease and cancer and we are able to make use of this valuable body of research to further explore the role of EndMT in AVM disease biology.

Together, this may be a potential determinant in patients’ risk for hemorrhage, a clinical factor that guides the choice of treatment plans.  We are currently establishing a study to further understand the contribution of these research findings in the presence of edema and hemorrhage in patients being admitted to Stanford. 

Development of in vitro Models of Disease

While several models of vascular malformations exist, it is unclear how accurately these reflect human AVMs.To further understand the disease biology and to test our hypotheses, we utilize human EC and smooth muscle cell cultures and have established cell lines from AVMs.  We have developed classic protein overexpression, proliferation and EC tube assays, and have a collaboration to introduce fluid flow.

And while we have yet to determine the initiating events in AVMs, this new finding highlights several avenues for treatment, as there are multiple drugs available to interrupt the process of EndMT, including some FDA-approved for other uses. We are actively working on developing an in vitro model to begin this level of testing.