Faculty and Research

Douglas Marchuk, PhD
Professor

Advances in our understanding of fundamental biological processes can be made by the analysis of defects manifested in inherited diseases. The genes responsible for these genetic syndromes encode proteins that act at critical points of the pathways that control fundamental biological processes. A genetic window to a biological process can be opened to reveal novel (previously unknown) genes, or novel roles for previously discovered gene products that are involved in these biochemical pathways.

My laboratory has taken this genetic approach to the study of one particular biological process, namely, vascular morphogenesis. We began with Mendelian disorders of vascular dysplasia and have progressed to more complex vascular phenotypes. Our objectives are twofold: (1) to provide basic knowledge on the role of these genes and gene products in vascular morphogenesis and (2) to gain specific knowledge of the pathology observed in these disorders.

The development and anatomy of the vascular system is highly ordered and exhibits a complex system of branching vessels. A similar complexity is observed in the anatomy of the vessels themselves, where in cross-section, the capillaries, veins and arteries each show different layers of cell types and extracellular components. Both the branching morphogenesis and the cross-sectional composition of the vascular system are under strict genetic control. We know this in part from developmental genetic studies using the mouse, where candidate genes are mutated and their effects on the embryonic vasculature are observed. Unfortunately, this gene deletion approach requires prior knowledge of these candidate genes, and often, some prior knowledge of their role in vascular biology.

Significantly, the importance of genetic control of vascular morphogenesis has also been demonstrated by human genetic research. Mendelian phenotypes have been described that show aberrant branching and/or cross-sectional anatomy, indicating strict genetic control of these processes. The identification of the genes underlying theses phenotypes has shed new light and understanding on the gene products and biochemical pathways that regulate vascular morphogenesis. Importantly, this human genetic approach represents an unbiased approach to the identification of genetic determinants of vascular morphogenesis. The identification of the gene requires no prior knowledge of the gene or its potential role in angiogenesis.

The first step in this approach is to identify the genetic loci that underlie these disorders. These mapping and positional cloning endeavors provide the basis for future molecular biological studies on the role of the mutant gene products in the pathology of the disease, and the role of the normal proteins in vascular development. These future investigations often require an in vivo model. The animal model serves as a tool to investigate the pathophysiology of the disease, and a more tractable system to begin to understand the biology of the gene product in vascular morphogenesis. Coming full circle, we can determine if the additional factors identified in the animal model also modify the clinical phenotype in the human disease. Our approach, and what we have learned about vascular morphogenesis using it, is discussed in a recently published review outlining much of our work (see "Vascular Morphogenesis: Tales of Two Syndromes:; Marchuk et al., 2003). We currently have three projects that utilize this approach, and a new initiative that begins with a mouse model of hypertrophic cardiomyopathy.