Cerebral Cavernous Malformations:  The Road from Gene Discovery to Potential Therapy

Dr. Douglas Marchuk, Director of the Division of Human Genetics at Duke University will be giving a talk to the Genetics Program on Monday, January 29, 2018, at 1:30 pm in 3503 Thomas Hall, Stephens Room. Dr. David Aylor, Genetics Program faculty member, will be hosting Dr. Marchuk.

The Marchuk lab has spent the last 22 years identifying genes that cause Mendelian syndromes of vascular dysmorphogenesis through its human studies. Researchers have identified seven different genes that cause a variety of vascular malformations (capillary malformations, venous malformations, arteriovenous malformations, cavernous malformations). They have learned that in addition to the inherited mutation, somatic mutations in these same genes appear to be required to initiate the focal lesion development. The Marchuk lab is continuing these genetic and genomic studies with vascular malformation tissue.

The Marchuk lab’s mouse studies are particularly interested in harnessing the power of mouse genetics to map novel genes that affect the severity and progression of disease in mouse models of disease. Researchers begin with an animal model of the disease, such as a surgically-induced or transgenic model of disease. The surgical intervention or the transgene acts as a sensitizer to create the disease in the animals. These sensitized models often exhibit drastically different rates of disease progression or outcome depending on the inbred strain employed.

Using genetic crosses with the sensitizer, scientists in this lab map and identify the genes underlying loci that influence disease outcome using both quantitative trait locus mapping and genome-wide association across many strains. Using this approach, researchers have identified genes and gene variants that drastically alter the phenotype and outcomes of mouse models of cardiomyopathy, ischemic stroke, and critical limb ischemia. The orthologs of the modifier genes discovered in the mouse models are further studied for their role in the disease pathology as well as investigated in the corresponding human disease populations by DNA sequencing and SNP association studies.

Douglas Marchuk received his Ph.D. from the University of Chicago in 1985. Dr. Marchuk is a James B. Duke Professor.


Seminar Title:
“Cerebral Cavernous Malformations:  The road from gene discovery to potential therapy”


Almost 20 years ago, exploiting a genetic founder effect in the Mexican-American population of the southwestern U.S.,  my lab identified a gene that causes an autosomal dominant condition called  Cerebral Cavernous Malformations, a cerebrovascular malformation leading to neurological complications including hemorrhagic stroke.   In the ensuing years, we identified another gene that when mutated, also causes inherited CCMs.   A third gene was identified by others.  We showed CCM lesion genesis is initiated by a somatic mutation of the remaining normal copy of the gene mutated in the germline, found in some (but not all) endothelial cells of the mature lesion. We later showed that this two-hit mutation paradigm was operative in sporadic (non-inherited) case as well, suggested a common pathogenesis for both the rarer, inherited forms and the more common sporadic forms.   Based on this genetic mechanism, we generated a mouse model of CCM disease that faithfully recapitulates the most clinically-relevant features of the human disease.  Work by others has identified a number of different signaling pathways that are aberrantly activated in CCM disease.  We have used our mouse model to investigate these pathways, and have shown that inhibition of at least one (Rho Kinase) can reduce lesion burden and hemorrhage in our mouse model, paving the way for clinical trials in human patients.