Advances in molecular biology, epidemiology, quantitative analysis and developmental biology have made it possible to identify genes involved in common complex traits in humans. Our laboratory applies these tools to study birth defects and prematurity. One project includes strategies to identify and characterize genes involved in cleft lip and palate, an inherited human birth defect. We have identified several genes involved in facial development and are studying their environmental covariates and clinical impact. For prematurity, a condition that causes 3 million deaths worldwide each year, we are using large sample collections and genome wide linkage and association to study thousands of individuals for millions of gene variants to generate enormous power for gene detection. Many of our studies are carried out using large population and epidemiologic studies of children , particularly from the Philippines, Japan, Denmark and Brazil, and we work in close collaboration with investigators in these countries. The studies of prematurity require clinical, biological and bioinformatic collaboration. We are also involved in studies of the prevention and better treatment of children with these disorders. Combining our molecular and developmental expertise with studies of epidemiology and environmental causes, holds out the promise for developing a better understanding of both rare disorders and common conditions. We are now developing strategies for prevention that include manipulation of genes or gene-environment interactions to prevent the primary occurrence of these tragic disorders. Graduate students serve in leadership roles for these projects and have primary responsibility for project design, implementation and publication. We are strongly committed to providing opportunities for students in the classroom, the laboratory and in fieldwork to develop their interests and expertise in the application of genetic tools to an understanding of human disease.
Dr. McCray has a long-standing interest in the pathogenesis and treatment of cystic fibrosis. His laboratory has two main areas of investigation: 1) innate mucosal immunity in the lung and how this is altered in disease states, and 2) gene transfer for the treatment of inherited diseases.
Studies of the anti-microbial properties of the airway surface liquid have stimulated interest in the anti-microbial proteins and peptides secreted by epithelia. Dr. McCray's lab is currently defining the tissue specific expression, regulation and anti-microbial activity of epithelial defensins and other proteins in model systems. These molecules may play a role in the innate mucosal immunity of the lung and other mucosal surfaces. A major effort is directed towards identifying novel host defense genes using genomics and large scale expression profiling.
Another area of investigation is the development of integrating viral vectors for the treatment of inherited diseases. Current projects include gene transfer to airway epithelia for cystic fibrosis and gene transfer to the hepatocytes for the treatment of hemophilia A. The focus of these studies is on the development and optimization of retrovirus-derived vectors. A long-term goal is to develop strategies with integrating vector systems that could be successfully used to treat genetic diseases.
Our research has diversified into two main areas: 1) How viruses infect and disseminate in skin; 2) How microbial and environmental factors play a role in the development of metabolic syndrome. Our prior research addressed how human cells senesce, leading to aging, and how they become immortal, leading to cancer, with a particular interest in on how human papillomaviruses transform cells. Our expertise in cell immortalization and cell culture techniques has allowed us develop 3D cell culture models that recapitulate human tissue for our research.
1) How viruses infect and disseminate in skin. Collaborative studies were recently initiated with Wendy Maury’s lab to examine how Ebola virus (EBOV) infects and transmits through human skin. We found that EBOV can infect and replicate in different skin cell populations. We are currently working to understand the course of infection in skin, what specific receptors are being utilized by EBOV in skin cells, and what role skin infection plays in transmission and pathogenesis.
2) How microbial and environmental factors play a role in the development of metabolic syndrome. Our success with immortalizing human preadipocytes (pre-fat) cells has led to studies on how environmental and bacterial toxins cause or exacerbate type II diabetes through effects on fat tissue. We found that dioxin-like polychlorinated biphenyls (PCBs), which are persistent organic pollutants, can disrupt adipogenesis (i.e. the development of functional fat cells) through activation of the aryl hydrocarbon receptor (AhR). This causes a proinflammatory response and inhibits master regulatory genes involved in adipogenesis. Endogenous microbial-derived tryptophan metabolites are also able to activate AhR. Studies are underway to determine the mechanism by which AhR activation disrupts adipogenesis and to develop 3D cultures and in vivo genetic models to assess the role of AhR in the development of metabolic syndrome.
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