My research interests include biochemical and molecular aspects of vitamin B12 / folate absorption, transport and metabolism; Genetic abnormalities of vitamin B12 / folate dependent pathways; Cellular and metabolic consequences of vitamin B12 and folate deficiencies; Vitamin B12, folate and homocysteine metabolism in the elderly population with cardio-vascular disease and cognitive disorders including Alzheimer’s dementia; Neuropathology of vitamin B12 and folate deficiency; B12, folate status and DNA methylation in the brain. Another area of research actively being pursued in my laboratory is the association of folate receptor autoimmunity with neural tube defect pregnancy and cerebral folate deficiency. Current research in my laboratory is focused on fetal and neonatal brain development and the role of folate and B12 in this process. We have established a strong link between an autoimmune disorder that produces autoantibodies against the folate receptor alpha, a membrane receptor involved in folate transport to the fetus and to the brain. The association of these autoantibodies in women during pregnancy can cause abnormal fetal brain development and in the newborn can affect brain function. A strong link has been established between the presence of folate receptor autoantibodies and autism spectrum disorders. Folinic acid treatment has helped alleviate many of the core behavioral deficits in autistic children with these autoantibodies. Research in my laboratory is aimed at understanding the cause and effects of this autoimmune disorder and how best to prevent and treat the pathologic consequences. While a test to identify folate receptor autoantibodies in serum has been developed, we are looking into developing novel markers to identify women at risk of having an autistic child and children at risk of developing autism. Another aspect of my research is focused on cancer therapeutics based on vitamin B12 and folate analogs that are anti-metabolites, drug-conjugates and pro-drugs; selective targeting of drugs via the B12 and folate transport proteins and their receptors; vitamin B12 and folate depletion strategies to inhibit cell replication in malignancies utilizing monoclonal antibodies to block cellular uptake of these vitamins and to deliver drugs. These approaches are designed to provide preferential targeting of rapidly dividing cancer cells because of the increased expression of receptors for uptake and increased need for these vitamins in cellular replication. In continuing our work on characterizing vitamin B12 binding proteins and the genes encoding these proteins, we are now studying the membrane receptor for the cellular uptake of vitamin B12. Having isolated the protein and gene encoding this receptor, we are now in a unique position to characterize this gene. It also provides us the tools for gene knockout studies that may finally yield valuable information on the role of vitamin B12 in embryogenesis, and the nervous system and perhaps identify the biochemical mechanism underlying the neuro-pathological manifestations of B12 deficiency which to date remains unexplained. Current Projects: 1. Folate receptor autoimmune disorder in folinic acid treatment. 2. Rat models of folate deficiency and folate receptor antibody exposure to identify their role in brain development and function. 3. The CD320 knockout model of B12 deficiency in the CNS. 4. Targeting the transcobalamin receptor (CD320) and the folate receptor (FRalpha)in cancer therapy.