About the Lab
Preventing Preventable Birth Defects
That is the overriding goal in the Finnell/Cabrera Birth Defects Research Laboratory. Our efforts focus on genetic susceptibility to environmentally induced complex congenital anomalies. To better resolve Gene X Environment Interactions, the laboratory uses a variety of genome editing approaches, stem cell biology and genomic interrogations of select global birth defect cohorts to glean insights into the prevention, understanding, and ultimately the treatment stemming from the consequences of complex birth defects. While the critical test of whether exposure to an exogenous substance causes human infants to be born with developmental or structural abnormalities must ultimately be tested in human populations, model organisms remain an important proxy for hypothesis testing in order to better understand the underlying molecular mechanisms that might represent pathways for intervention to prevent these preventable birth defects. Over the years we have developed extensive collaborations with the CDC funded National Birth Defect Prevention Study, of which our laboratory processes and maintains the DNA samples from Texas, California, and Massachusetts. We have extensive ongoing global field studies throughout China at multiple clinical and research centers and in Nicaragua. We are serving as the co-founding coordinators of a global neural tube defect network to promote sample and data sharing to enhance to development of robust sized cohort of NGS sequenced NTD samples for direct, translational studies to help families reach their reproductive goals and hopefully prevent, preventable birth defects.
Using Model Organisms
Genetically modified mice represent outstanding tools for developing and directly testing hypotheses about environmental factors that cause birth defects. The laboratory makes use of a variety of such mice to understand the mechanism by which nutrients such as folic acid prevents common birth defects, including neural tube (Spina bifida) and heart defects (conotruncal defects). We have applied both conventional and conditional knockout mouse models of genes specifically involved in folate metabolism and transport (e.g., Folr1, Folr2, Folr4, Rfc1, Slc25a32, Mthfd1l, Mthfr and Pcft) to these birth defect studies. We have also generated novel mice for GCPR genes (GPR161) and those involved in planar cell polarity (Fuz) that are relevant NTD models. These mouse tools are an invaluable resource as we try to learn how nutritional factors prevent certain birth defects and promote the development of healthy babies. In a knockout mouse, we eliminate one gene-usually a gene that brings a vitamin into a cell-and then determine its impact on embryogenesis. For example, when we inactivate (knock out) the folate receptor (Forl1) gene-its protein product which is a receptor molecule that brings vitamin B9 (folic acid) into cells is eliminated, and the newborn pups present with neural, cardiac and craniofacial defects.
We can then investigate cellular events that are occurring in order to elucidate other potential interventions for non-folate responsive birth defects in our ongoing efforts to prevent preventable birth defects. We make these mice and related reagents available to researchers around the world so that they can apply their particular skills to learn more about the causes of nutrition-related birth defects. Interestingly, while not all cells have folate receptors, essentially all cancer cells do. So many new drugs to fight cancer are being developed in such a way that a cytotoxic molecule is linked to folic acid. When they are administered to the person (or animal), the folic acid is bound by the folate receptor, which is on the cancer cells more often than on healthy cells, and so the toxic drugs are more effectively targeted directly to the cancer cells. This is especially true for ovarian cancer, so we are working with collaborators to help them develop such highly efficacious drugs and our mice which lack these folate receptors are the perfect tool for them to test the effectiveness of candidate compounds. The ultimate goals short of total prevention of all birth defects would be to develop effective treatments for those children born with structural malformations. We have set forth on a program of highly translational research using mice and sheep models of spina bifida to utilize information gained from genomic studies to activate select developmental pathways using stem cells or neurotrophic or growth factors to treat neurogenic bladder and bowel issues secondary to spina bifida.
We have been using what we have learned from our model organism studies to develop new prenatal diagnostic tests to identify and help manage high-risk pregnancies. We discovered that there were high titers of antibodies to the folate receptor alpha protein among mothers who were pregnant with spina bifida affected infants. These blocking antibodies were thought to restrict folate transport to the placenta and developing embryo at critical periods during neural tube closure, increasing the risk for spina bifida and perhaps other birth defects. We have expanded this to see if autoantibodies to folate receptor alpha is a good prenatal test for other neurodevelopmental anomalies and adverse reproductive outcomes including: cerebral folate deficiency syndrome, congenital heart defects, preeclampsia, and low birth weight infants. We are involved in all of the largest genomic studies of neural tube defects in order to better define the genetic architecture of these complex birth defects in an effort to identify novel pathways that might be better suited for intervention strategies than those that are currently known and appreciated.
Of very recent importance is the possible role of folates and the folate receptors (FOLR1 and FOLR2) in the morbidity and mortality associated with the COVID-19 virus. Considering what we know about folates and homocysteine, where high levels of folates produce low levels of homocysteine and the reverse, and that both homocysteine and its thiolactone metabolite produce protein precipitation plaques that are associated with cardiovascular disease, it is possible that understanding the role of the folate receptor in the respiratory system could have therapeutic implications. We need to determine why there are high expression levels of folate receptors in the lung and what their role is there. Should there be folate-COVID-19 interactions, do they have any impact on disease severity or lethality? It would be important to determine if there are more deaths in countries that do not fortify with folic acid. These experiments will aid in our understanding of the consequences of COVID-19 infection.